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Gender and post-ischemic recovery of hypertrophied rat hearts Saeedi, Ramesh; Wambolt, Richard B; Parsons, Hannah; Antler, Christine; Leong, Hon S; Keller, Angelica; Dunaway, George A; Popov, Kirill M; Allard, Michael F Mar 1, 2006

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ralssBioMed CentBMC Cardiovascular DisordersOpen AcceResearch articleGender and post-ischemic recovery of hypertrophied rat heartsRamesh Saeedi1, Richard B Wambolt1, Hannah Parsons1, Christine Antler1, Hon S Leong1, Angelica Keller2, George A Dunaway3, Kirill M Popov4 and Michael F Allard*1Address: 1James Hogg iCAPTURE Centre for Cardiovascular and Pulmonary Research, Department of Pathology and Laboratory Medicine, University of British Columbia-St Paul's Hospital, Vancouver, BC, V6Z 1Y6, Canada, 2Labatoire CRRET, Faculté des Sciences, Université de Paris XII, Creteil Cedex, 94010, France, 3Department of Pharmacology, Southern Illinois University School of Medicine, Springfield, IL, 62794, USA and 4Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, AL 35294, USAEmail: Ramesh Saeedi - rsaeedi@mrl.ubc.ca; Richard B Wambolt - rwambolt@mrl.ubc.ca; Hannah Parsons - hparsons@mrl.ubc.ca; Christine Antler - cantler@mrl.ubc.ca; Hon S Leong - hleong@mrl.ubc.ca; Angelica Keller - keller@univ-paris12.fr; George A Dunaway - gdunaway@siumed.edu; Kirill M Popov - kpopov@uab.edu; Michael F Allard* - mallard@mrl.ubc.ca* Corresponding author    AbstractBackground: Gender influences the cardiac response to prolonged increases in workload, with differences at structural,functional, and molecular levels. However, it is unknown if post-ischemic function or metabolism of female hypertrophiedhearts differ from male hypertrophied hearts. Thus, we tested the hypothesis that gender influences post-ischemicfunction of pressure-overload hypertrophied hearts and determined if the effect of gender on post-ischemic outcomecould be explained by differences in metabolism, especially the catabolic fate of glucose.Methods: Function and metabolism of isolated working hearts from sham-operated and aortic-constricted male andfemale Sprague-Dawley rats before and after 20 min of no-flow ischemia (N = 17 to 27 per group) were compared.Parallel series of hearts were perfused with Krebs-Henseleit solution containing 5.5 mM [5-3H/U-14C]-glucose, 1.2 mM[1-14C]-palmitate, 0.5 mM [U-14C]-lactate, and 100 mU/L insulin to measure glycolysis and glucose oxidation in one seriesand oxidation of palmitate and lactate in the second. Statistical analysis was performed using two-way analysis of variance.The sequential rejective Bonferroni procedure was used to correct for multiple comparisons and tests.Results: Female gender negatively influenced post-ischemic function of non-hypertrophied hearts, but did notsignificantly influence function of hypertrophied hearts after ischemia such that mass-corrected hypertrophied heartfunction did not differ between genders. Before ischemia, glycolysis was accelerated in hypertrophied hearts, but to agreater extent in males, and did not differ between male and female non-hypertrophied hearts. Glycolysis fell in all groupsafter ischemia, except in non-hypertrophied female hearts, with the reduction in glycolysis after ischemia being greatestin males. Post-ischemic glycolytic rates were, therefore, similarly accelerated in hypertrophied male and female heartsand higher in female than male non-hypertrophied hearts. Glucose oxidation was lower in female than male hearts andwas unaffected by hypertrophy or ischemia. Consequently, non-oxidative catabolism of glucose after ischemia was lowestin male non-hypertrophied hearts and comparably elevated in hypertrophied hearts of both sexes. These differences innon-oxidative glucose catabolism were inversely related to post-ischemic functional recovery.Conclusion: Gender does not significantly influence post-ischemic function of hypertrophied hearts, even though femalesex is detrimental to post-ischemic function in non-hypertrophied hearts. Differences in glucose catabolism mayPublished: 01 March 2006BMC Cardiovascular Disorders2006, 6:8 doi:10.1186/1471-2261-6-8Received: 23 November 2005Accepted: 01 March 2006This article is available from: http://www.biomedcentral.com/1471-2261/6/8© 2006Saeedi et al; licensee BioMed Central Ltd.This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Page 1 of 13(page number not for citation purposes)contribute to hypertrophy-induced and gender-related differences in post-ischemic function.BMC Cardiovascular Disorders 2006, 6:8 http://www.biomedcentral.com/1471-2261/6/8BackgroundThere is substantial clinical and experimental evidence toindicate that gender influences the myocardial response tohemodynamic overload with female sex having a benefi-cial effect [1-5]. In the clinical setting, for example, studieshave reported that females have increased cardiac hyper-trophy, more concentric remodelling, and better preserva-tion of left ventricular systolic function than males inresponse to increased hemodynamic load, such as occurswith aortic stenosis or hypertension [4,5]. Experimentalstudies have also found differences in geometric remodel-ling and cardiac function between hypertrophied heartsfrom males and females similar to those observed inhumans [1-3]. This gender-related preservation of func-tion in the setting of cardiac hypertrophy, which is a lead-ing risk factor for development of heart failure [6],translates into a lower overall incidence of heart failure infemales than in males [7].Despite having a beneficial effect on cardiac remodellingdue to hemodynamic overload, female sex is associatedwith greater rates of heart failure in the presence of symp-tomatic coronary artery disease [7,8]. This finding is con-sistent with clinical data indicating that, although oflower incidence in women, coronary artery disease is par-ticularly problematic once present. Correspondingly,females have an increased risk of a poor outcome aftercoronary revascularization procedures [7,9,10] andyounger women have worse short-term outcomes afteracute myocardial ischemia leading to infarction than men[11,12]. Furthermore, the presence of left ventricularhypertrophy has been shown to have a detrimentalimpact on mortality due to ischemic heart disease that isgreater in women than in men [13]. Taken together, thesedata indicate that female sex influences remodelling dueto hemodynamic overload as well as outcome afterischemia. They also suggest that the functional signifi-cance of simultaneously occurring cardiac hypertrophyand coronary artery disease differs between women thanin men.Cardiac hypertrophy due to hemodynamic overload hasgenerally been viewed as an adaptive response [14,15].However, it can also be considered maladaptive. This lat-ter consideration becomes especially apparent whenhypertrophied hearts are exposed to ischemia and reper-fusion, a situation that results in significantly lower post-ischemic heart function in hypertrophied hearts than innon-hypertrophied hearts [16-19]. Currently, the detri-mental effect of hypertrophy on post-ischemic heart func-tion is well documented in hypertrophied hearts frommales. To our knowledge, functional outcome of pressure-overload hypertrophied hearts after ischemia in femalesknown with certainty. Such information would provideimportant insights into the apparent additive effects ofcardiac hypertrophy and ischemic heart disease in femalesobserved clinically.As in non-hypertrophied hearts [20], the catabolic fate ofexogenous glucose is recognized as an important factorthat contributes to the poor post-ischemic function ofhypertrophied hearts, at least in hypertrophied heartsfrom males [16-19,21,22]. Specifically, the extent towhich glucose passing through glycolysis is catabolizednon-oxidatively (i.e, is converted to lactate rather to CO2)appears to be of functional significance, as rates of non-oxidative glycolysis are inversely related to post-ischemicfunction of male hypertrophied and non-hypertrophiedhearts [22]. An acceleration of overall glycolysis combinedwith a limitation of glucose oxidation [19,23,24] result inincreased rates of non-oxidative glycolysis in hypertro-phied male hearts [22]. That accelerated rates of non-oxi-dative glycolysis contribute to the poor outcome ofhypertrophied hearts after ischemia is supported by datashowing that stimulation of glucose oxidation and/orreduction of glycolysis, effects that alone or in combina-tion reduce non-oxidative glycolysis, substantiallyimprove function of ischemic-reperfused hypertrophiedhearts from male rats [19,22]. At this time, it is not yetclearly known if female gender influences the pattern ofsubstrate use and particularly of glucose use in pressure-overload hypertrophied hearts either before or afterischemia.In the experiments described here, we tested the hypothe-sis that gender influences post-ischemic functional recov-ery of pressure-overload hypertrophied hearts. Given theimportance of substrate use to post-ischemic recovery ofhypertrophied heart function in males, we also deter-mined if substrate use in female hypertrophied hearts dif-fered from that in male hypertrophied hearts and, if so,whether any differences could be explained by alterationin expression or activity of key enzymes and proteinsinvolved in control of myocardial substrate use.MethodsAnimal modelA mild pressure-overload left ventricular hypertrophy wasproduced in male and female Sprague-Dawley rats by con-striction of the suprarenal abdominal aorta with a metal-lic clip (0.4 and 0.3 mm diameter, respectively) at 3 weeksof age [23]. In sham-operated control rats, the aorta wasisolated, but not clipped. Experiments were performed 8weeks after surgery. Food and water were administrated adlibitum. These experiments were approved by the institu-tional committee on the use of laboratory animals inPage 2 of 13(page number not for citation purposes)and whether cardiac hypertrophy is more or less detri-mental to outcome in females than in males are not yetresearch and conform with the Guide for the Care and UseBMC Cardiovascular Disorders 2006, 6:8 http://www.biomedcentral.com/1471-2261/6/8of Laboratory Animals by the US National Institutes ofHealth (NIH Publication No. 85-23, revised 1986).A subset of anesthetized (ketamine/xylazine, 90/10 mg/kg, IP) male and female rats with and without aortic con-striction were studied 8 weeks after surgery in order todetermine if gender influenced the pressure load in thismodel. Mean arterial pressure and heart rate were deter-mined by means of a micromanometer-tipped catheter(SPR-838, Millar Instruments, Houston, TX) in the leftcarotid artery.Isolated heart preparation and perfusion protocolAs previously described [19,23], isolated working heartsfrom aortic-constricted and sham-operated rats were per-fused at a left atrial preload of 11.5 mmHg and an aorticafterload of 80 mmHg in a closed recirculating systemwith oxygenated (95% O2-5% CO2) Krebs-Henseleit (KH)solution. Hearts were all perfused under comparable con-ditions in order to avoid potentially confounding effectsof exposure to different afterloads. Although hearts fromaortic-constricted rats are exposed to elevated afterloads invivo, we have shown that adjusting afterload to normalizecoronary flow per gram in isolated working hypertrophiedhearts does not significantly influence the functional ormetabolic outcomes observed after ischemia [25]. The KHsolution contained 1.2 mM palmitate prebound to fattyacid-free albumin (3%), 5.5 mM glucose, 0.5 mM lactate,2.5 mM calcium, and 100 mU/l insulin and was main-tained at 37°C. A high physiologic concentration of insu-lin was used in order to ensure that insulin-dependentglucose uptake was not limiting. The concentration ofpalmitate was chosen in order to recapitulate conditionsobserved during reperfusion after ischemia [20]. Heartrate, peak systolic pressure, cardiac output and aortic flowwere measured every 10 min of the working heart per-fusion. Coronary flow and indices of external cardiacwork, including rate-pressure product and hydraulicpower, were calculated as described [19,23].Hearts were initially perfused for 30 min under normoxicnon-ischemic conditions followed by a 20 min period ofglobal ischemia that was induced by clamping both theleft atrial preload and aortic afterload lines. At the end ofischemia, the clamps were removed and the hearts werereperfused for 40 min. We have previously shown thatfunction is stable in isolated working hearts perfusedunder non-ischemic, normoxic conditions for 90 min[26]. At the end of reperfusion, hearts were quickly frozenusing tongs cooled to the temperature of liquid nitrogen.Frozen heart tissue was weighed with a portion of ven-tricular tissue used to determine the dry-to-wet tissueweight ratio.Measurement of myocardial substrate utilization and glycogen contentMyocardial substrate utilization was measured in two par-allel series in each group. In the first series of experiments,hearts were perfused with [5-3H]-glucose and [U-14C]-glu-cose in order to determine rates of glycolysis and glucoseoxidation, respectively, as previously described [23,27]. Inthe second series of experiments performed under identi-cal conditions, rates of lactate and palmitate oxidationwere determined by perfusing the hearts with [U-14C]-lac-tate and [9,10-3H] palmitate [23,27]. It should be notedthat these rates refer to catabolic rates of exogenous sub-strates, as the contribution of endogenous substrates, suchas glycogen, was not taken into account. Rates of glycoly-sis and palmitate oxidation were determined by quantita-tively measuring the rate of 3H2O production. Rates ofglucose and lactate oxidation were measured by quantita-tive collection of 14CO2 released as a gas and dissolved inthe perfusate as [14C]-bicarbonate. Perfusate and gaseoussamples were taken every 10 min of perfusion and wereultimately placed in vials containing scintillation cocktailand counted by standard techniques. Pre-ischemic valuesfor all metabolic rates were calculated based on data col-lected between 10 and 30 min, while post-ischemic valueswere calculated between 10 and 40 min of reperfusion.Rates of non-oxidative glycolysis were calculated as thedifference between rates of glycolysis and glucose oxida-tion [22]. Myocardial glycogen was determined by meas-uring glucose obtained following digestion of frozenpowdered ventricular tissue with 30% KOH, ethanol pre-cipitation, and acid hydrolysis of glycogen [28].Content and activity of selected myocardial metabolic proteins and pnzymesThe content of selected enzymes and proteins involved incontrol of myocardial substrate utilization was deter-mined by immunoblot analysis using a previouslydescribed method [26,29]. The particular proteins andenzymes assessed were chosen based upon either recogni-tion as having significant control strength for the meta-bolic pathway in question and/or reported alteration inmodels of cardiac hypertrophy. Briefly, samples of frozenventricular tissue homogenate (containing 20 µg totalprotein) were solubilized by boiling in reducing samplebuffer, separated by electrophoresis on 10% SDS-polyacr-ylamide gels, and transferred by electroblotting to a nitro-cellulose membrane. After non-specific blocking, theblots were probed overnight with the following primaryantibodies: rabbit anti-GLUT-4 (1:1500 dilution, Cell Sig-nalling Technology, Missisauga, Ontario), mouse anti-glyceraldehyde-3-phosphate dehydrogenase (GAPDH,1:200,000 dilution, Molecular Probes, Eugene, Oregon),rabbit anti-α- and β-enolase (1:5,000 and 1:75,000 dilu-Page 3 of 13(page number not for citation purposes)tion, respectively [30], rabbit anti-muscle type phosphof-ructokinase (PFK, 1:3,000 dilution [31], rabbit anti-BMC Cardiovascular Disorders 2006, 6:8 http://www.biomedcentral.com/1471-2261/6/8pyruvate dehydrogenase complex (PDC, 1:4,000 dilution,[32], rabbit anti-medium-chain (MCAD, 1:4,000 dilu-tion) and anti-long-chain (LCAD, 1:5,000 dilution) acyl-CoA dehydrogenases [33]. After incubation with theappropriate secondary antibody, the signal was detectedby an ECL based detection system. Band intensity valuesfor each individual protein were quantified by densitom-etry. For each protein of interest, GAPDH was sequentiallydetected for purposes of normalization. Background-cor-rected densitometry values for the protein of interest andGAPDH were used to calculate relative expression ratios.Activity of PDC was determined as described [32].Statistical analysisAnalysis was performed using SPSS version 7.0. Weight,glycogen, expression, and activity data were analyzedusing two-way analysis of variance (ANOVA). Left ven-tricular function, glycolysis, and oxidation of glucose, lac-tate, and palmitate were examined using two-wayrepeated measures ANOVA. A log transformation of datawas used, when necessary, to satisfy homogeneity of vari-ance assumption for ANOVA. The sequential rejectiveBonferroni procedure was used to correct for multiplecomparisons and tests. A corrected p value > 0.05 was con-sidered as non-significant. Data are expressed as meansvalue ± SEM.ResultsAnimal modelMorphologic and in vivo hemodynamic data are summa-rized in Table 1. Eight weeks after surgery, heart weight inmale and female aortic constricted rats was approximately20% greater than sex-matched sham-operated controlrats. There was no significant difference in body weightbetween aortic-constricted and sham-operated rats ofeither sex. Heart and body weights of female rats were sig-nificantly lower than that of male rats. As with heartweight, the ratio of heart weight and body weight showeda comparable percent increase in both male (20.1 ± 2.3%)and female (24.0 ± 1.9%, p = NS) aortic-constricted rats.Aortic constriction resulted in significant increases inmean aortic pressure in both male and female rats but hadno effect on heart rate. Mean aortic pressure did not differbetween male and female sham-operated control rats orbetween male and female rats with aortic constriction.Heart functionHeart function is summarized in Table 2. Before ischemia,cardiac output, hydraulic power, and coronary flow werelower in male hypertrophied hearts than correspondingvalues in male non-hypertrophied hearts. In contrast,only coronary flow was lower in hypertrophied heartsfrom female rats than in non-hypertrophied hearts fromfemale rats. Other than higher coronary flow rates infemales, there were no significant differences in functionbetween male and female hypertrophied hearts. In non-Table 1: Morphologic and hemodynamic data of hearts from sham-operated and aortic-constricted rat heartsMale FemaleControl Hypertrophy Control HypertrophyBody wt (g) 451 ± 5 453 ± 10 278 ± 5$ 271 ± 5*$Heart wt (g) 1.86 ± 0.02 2.23 ± 0.04* 1.28 ± 0.04$ 1.55 ± 0.03*$Heart/body wt 4.1 ± 0.04 4.95 ± 0.09* 4.61 ± 0.11$ 5.72 ± 0.09*$Heart rate (bpm) 262.5 ± 7.4 255.8 ± 3.0* 260.4 ± 10.1 255.4 ± 10.5*Mean aortic pressure (mm Hg) 109.6 ± 7.0 164.6 ± 7.3 96.3 ± 6.0 153.1 ± 5.8Values are Mean ± SEM. Sham-operated rats, Control. Aortic-constricted rats, Hypertrophy. Numbers for morphologic data are 18–36 per group and for hemodynamic data are 6–8 per group; * vs. Sex-matched Control, p < 0.05; $vs. corresponding Male value, p < 0.05.Table 2: Heart function data in hearts from sham-operated and aortic-constricted rat heartsMale Control Male Hypertrophy Female Control Female HypertrophyPre-I Post-I Pre-I Post-I Pre-I Post-I Pre-I Post-IHeart Rate (bpm) 253 ± 4 261 ± 5 247 ± 5 242 ± 10 250 ± 3 214 ± 7#$ 251 ± 5 182 ± 11#*$Peak Systolic Pressure (mmHg) 111 ± 1 100 ± 2# 109 ± 2 95 ± 2# 108 ± 1 91 ± 4# 108 ± 1 89 ± 4#$Cardiac Output (ml/min) 69 ± 2 47 ± 3# 56 ± 2* 31 ± 4#* 55 ± 1$ 25 ± 2#$ 53 ± 2 20 ± 2#$Coronary Flow (ml/min g wet wt) 16 ± 1 13 ± 1# 10 ± 1* 6 ± 1#* 20 ± 1$ 11 ± 1#$ 14 ± 1*$ 6 ± 1#*Rate Pressure Product (bpm × mmHg × 10-3) 28 ± 1 26 ± 1# 27 ± 1 24 ± 1#* 27 ± 1 20 ± 1#$ 27 ± 1 17 ± 1#$Hydraulic Power (ml/min × mmHg × 10-3) 77 ± 3 48 ± 4# 62 ± 3* 30 ± 4#* 59 ± 2$ 24 ± 2#$ 57 ± 2 19 ± 2#*$Page 4 of 13(page number not for citation purposes)Values are Mean ± SEM. Non-hypertrophied heart, Control. Hypertrophied heart, Hypertrophy. Pre-I, Pre-ischemia; Post-I, Post-ischemia; *, vs Sex-matched Control; #, vs pre-Ischemic values; $, vs corresponding Male value; all at p < 0.05.BMC Cardiovascular Disorders 2006, 6:8 http://www.biomedcentral.com/1471-2261/6/8hypertrophied hearts, cardiac output and hydraulic powerwere higher in males than in females, while coronary flowwas highest in females.Functional parameters, except for heart rate in males, werereduced in all groups after ischemia as compared to corre-sponding pre-ischemic values. Post-ischemic function ofhypertrophied hearts from both male and female rats waslower than corresponding non-hypertrophied hearts.Hypertrophied heart function after ischemia in femaleswas lower than that in male hypertrophied hearts, exceptfor post-ischemic coronary flow rates which did not differbetween male and female hypertrophied hearts. All func-tional parameters in reperfused female non-hypertro-phied hearts, except peak systolic pressure, weresignificantly lower than those in male non-hypertrophiedhearts during reperfusion. The differences in post-ischemic function between male and female heartsremained when function was corrected for heart weight(Figure 1), except that function during reperfusion nolonger differed significantly between male and femalehypertrophied hearts. Compared to pre-ischemic values,recovery of function was lower in female hypertrophied(33.4 ± 4.1%) and non-hypertrophied (40.2 ± 4.3%)0.05). When external cardiac work is expressed relative togender-matched non-hypertrophied hearts as a means toaccount for gender-related differences in function, post-ischemic functional recovery is comparably reduced inmale (77.0 ± 9.5%) and female (83.0 ± 10.1%) hypertro-phied hearts as compared to pre-ischemic values indicat-ing that the impact of hypertrophy on post-ischemicrecovery is similar in both genders.Myocardial substrate utilizationGlycolysisPrior to ischemia, glycolysis was higher in hypertrophiedhearts than in non-hypertrophied hearts from male andfemale rats (Figure 2A). Rates of glycolysis were greater inhypertrophied hearts from males than from females,while differences in glycolysis were not observed betweenmale and female non-hypertrophied hearts. Afterischemia, rates of glycolysis were significantly lower thanpre-ischemic values in all groups except non-hypertro-phied hearts from female rats. Glycolysis was, therefore,higher in female non-hypertrophied hearts than in malenon-hypertrophied hearts. Rates of glycolysis continuedto be accelerated in hypertrophied hearts after ischemia inmales and females with rates in male and female hypertro-phied hearts no longer significantly different.Glucose oxidationBefore ischemia, glucose oxidation was higher in malenon-hypertrophied and hypertrophied hearts than in cor-responding hearts from female rats (Figure 2B). Rates inhypertrophied hearts did not differ from those in non-hypertrophied hearts in either sex. Glucose oxidation afterischemia was not different from rates before ischemia inany group.Palmitate oxidationPrior to ischemia, rates of palmitate oxidation wereapproximately 30% lower in hypertrophied hearts than innon-hypertrophied hearts from both male and female rats(Figure 2C). Sex of the animal did not influence palmitateoxidation rates in either non-hypertrophied or hypertro-phied hearts before ischemia. In males, post-ischemicrates of palmitate oxidation in hypertrophied and non-hypertrophied hearts did not differ from those beforeischemia. In contrast, palmitate oxidation decreased inhearts from female rats after ischemia compared to pre-ischemic values such that palmitate oxidation was signifi-cantly lower in hypertrophied hearts from females than inmale hypertrophied hearts.Lactate oxidationCompared to corresponding non-hypertrophied hearts,lactate oxidation before ischemia was lower in malePost-ischemic mass-corrected function of hypertrophied and n n-hypertrophied hea ts from male and female ratsFigure 1Post-ischemic mass-corrected function of hypertrophied and non-hypertrophied hearts from male and female rats. Open circle, male non-hypertrophied hearts; open square, male hypertrophied hearts; filled circle, female non-hypertrophied hearts; filled square, female hypertrophied hearts. *, vs. sex-matched non-hypertrophied hearts (p < 0.05). #, vs. corre-sponding male hearts (p < 0.05). Numbers per group: 27 male non-hypertrophied hearts, 21 male hypertrophied hearts, 17 female non-hypertrophied hearts, and 18 female hypertrophied hearts. Values are mean ± SEM.01020300 10 20 30 40Time (min)(ml/min x mmHg / 1000 x g wet wt)* *### #*** **Heart FunctionPage 5 of 13(page number not for citation purposes)hearts than in corresponding male hypertrophied (48.4 ±6.2%) and non-hypertrophied (64.4 ± 4.5%) hearts (p <hypertrophied hearts but was not different in femalehypertrophied hearts (Figure 2D). Rates of lactate oxida-BMC Cardiovascular Disorders 2006, 6:8 http://www.biomedcentral.com/1471-2261/6/8tion were higher in male than in female non-hypertro-phied hearts. Lactate oxidation, therefore, did not differ inhypertrophied hearts from male and female rats. In malehypertrophied hearts, lactate oxidation after ischemia didnot differ from that before ischemia. Lactate oxidationafter ischemia increased in female hearts as compared topre-ischemic values, achieving significance only in hyper-trophied hearts. Post-ischemic rates of lactate oxidation inNon-oxidative glycolysisPrior to ischemia, non-oxidative glycolysis was higher inhypertrophied hearts than corresponding non-hypertro-phied hearts in both sexes with rates in hypertrophiedhearts from males greater than those from females (Table3). Rates did not differ between male and female non-hypertrophied hearts. Non-oxidative glycolysis was higherin hypertrophied hearts than non-hypertrophied heartsGlycolysis (A), glucose oxidation (B), palmitate oxidation (C), and lactate oxidation (D) in hypertrophied and non-hypertro-phied hearts from male an  female ratsFigure 2Glycolysis (A), glucose oxidation (B), palmitate oxidation (C), and lactate oxidation (D) in hypertrophied and non-hypertro-phied hearts from male and female rats. White bar, male non-hypertrophied hearts; black bar, male hypertrophied hearts; light grey bar, female non-hypertrophied hearts; dark grey bar, female hypertrophied hearts. *, vs. sex-matched non-hypertrophied hearts at same time period (p < 0.05). #, vs. pre-ischemic value (p < 0.05). $, vs. corresponding male hearts at same time period (p < 0.05). Numbers per group: 12 to 16 male non-hypertrophied hearts, 8 to 14 male hypertrophied hearts, and 6 to 8 female non-hypertrophied hearts, 6 to 8 female hypertrophied hearts. Values are mean ± SEM.D)C)Pre-Ischemia Post-Ischemianmol/min/g dry wt0300600900* **## $ *Pre-Ischemia Post-Ischemianmol/min/g dry wt0250500750* *# $$Pre-Ischemia Post-Ischemianmol/min/g dry wt0160320480$$ $$B)A)Pre-Ischemia Post-Ischemianmol/min/g dry wt0180036005400*$###$* **Lactate OxidationGlucose OxidationPalmitateOxidationGlycolysisPage 6 of 13(page number not for citation purposes)female hypertrophied hearts were now higher than thosein hypertrophied hearts from male rats.but rates no longer differed between male and femalehypertrophied hearts after ischemia. On the other hand,BMC Cardiovascular Disorders 2006, 6:8 http://www.biomedcentral.com/1471-2261/6/8rates of post-ischemic non-oxidative glycolysis were sig-nificantly higher in non-hypertrophied hearts fromfemales than from males. Of importance, recovery ofheart function after ischemia showed a significant inverserelationship with rates of non-oxidative glycolysis (Figure3).Myocardial glycogenContent of glycogen did not differ between non-hypertro-phied and hypertrophied hearts at the end of reperfusionin either males (136 ± 10 vs. 152 ± 9 µmol/g dry wt, p =NS) or females (118 ± 12 vs. 110 ± 8 µmol/g dry wt, p =NS). Myocardial glycogen was lower in female hearts thanin male hearts, but was significantly lower only in femalehypertrophied hearts as compared to male hypertrophiedhearts (p < 0.05).Myocardial content and activity of selected metabolic proteins and enzymesDifferences in expression of key enzymes and proteinsinvolved in glucose and fatty acid metabolism were notobserved between male hypertrophied and non-hypertro-phied hearts (Figures 4 and 5). In contrast, expression ofPFK-1 and enolase-β was increased and decreased, respec-tively, in female hypertrophied hearts compared to non-hypertrophied hearts from female rats (Figures 4 and 6).As in males, differences in expression of MCAD and LCADwere not observed between female hypertrophied andnon-hypertrophied hearts (Figure 5). Only minor sex-related differences in myocardial expression of these pro-teins and enzymes were detected (Figure 6). Specifically,expression of enolase-α, relative to GAPDH, was higher,while that of PDC E1α was lower in male hearts than infemale hearts, regardless of the presence or absence ofhypertrophy. Activity of PDC was not significantly differ-ent between hypertrophied and non-hypertrophied heartsin males (16.10 ± 2.27 vs. 14.48 ± 0.28 nmol min-1 mgprotein-1) or females (12.60 ± 1.12 vs. 15.97 ± 5.08 nmolmin-1 mg protein-1). There were also no significant genderrelated differences in activity of PDC.DiscussionGender, hypertrophy, and heart functionoverload hypertrophied hearts. Differences in post-ischemic function occurred largely because female sex wasassociated with greater dysfunction after ischemia thanmale sex. Interestingly, when compared to sex-matchednon-hypertrophied hearts, the degree of functionalimpairment in female hypertrophied hearts was compara-ble to that in male hypertrophied hearts (Table 2 and Fig-ure 1), indicating that the detrimental effect ofhypertrophy on function after acute ischemia is similar infemales than in males.Few experimental studies have specifically compared thefunctional outcome of non-hypertrophied hearts fromRelationship of post-ischemic contractile function to rates of non-oxidative glycoly is in hypertrophied a d non-hypertr -phied hearts from male a d female ra sFigure 3Relationship of post-ischemic contractile function to rates of non-oxidative glycolysis in hypertrophied and non-hypertro-phied hearts from male and female rats. Percent (%) Recov-ery of left ventricular external work was calculated as the quotient of post-ischemic and pre-ischemic hydraulic power multiplied by 100. Non-oxidative glycolysis was calculated as the difference between rates of glycolysis and glucose oxida-tion. Regression analysis was performed using data from indi-vidual hearts (N = 33 hearts; R = -0.49, p < 0.05) and is expressed as mean data per group (N = 5 to 12 per group). Values are mean ± SEM. Open circle, Male Control. Closed circle, Male hypertrophy. Open square, Female Control. %Recovery of left ventricular external work (%)Non-oxidative glycolysis (nmol/min/g dry wt)03060900 1000 2000 3000 4000*$*Table 3: Non-oxidative glycolysis in hearts from sham-operated and aortic-constricted ratsMale FemaleControl Hypertrophy Control HypertrophyPre-ischemic 2504 ± 180 4224 ± 231* 2274 ± 167 3017 ± 152*$Post-ischemic 1259 ± 109# 2748 ± 187#* 2011 ± 144$ 2595 ± 144#*Values are Mean ± SEM. Sham-operated rats, Control. Aortic-constricted rats, Hypertrophy. Numbers are 5–18 per group; * vs. Sex-matched Control, p < 0.05; $ vs. corresponding Male heart at the same time period, p < 0.05; # vs. pre-ischemic value, p < 0.05.Page 7 of 13(page number not for citation purposes)In the current study, gender was not found to significantlyinfluence post-ischemic recovery of function in pressureClosed square, Female Hypertrophy.BMC Cardiovascular Disorders 2006, 6:8 http://www.biomedcentral.com/1471-2261/6/8males and females after ischemia and reperfusion. Inkeeping with our results, Glick et al [34] found that post-ischemic functional recovery of isolated working heartsfrom female rats is lower than that of hearts from malerats when hearts are perfused with a solution containingglucose and fatty acid, a heart preparation and a perfusatecomposition very similar to that used in the current inves-tigation. Our finding of a reduced functional recovery infemale hearts after ischemia is also consistent with clinicaldata showing that women are at greater risk than men ofa poor outcome after myocardial ischemia or revasculari-zation procedures [7,9-12].Gender-related differences in function of hypertrophiedand non-hypertrophied hearts prior to ischemia were alsoobserved. Pre-ischemic function of hypertrophied heartsclinical [1,4,35] and experimental [1-3] studies showingthat female gender beneficially influences the myocardialresponse to hemodynamic overload. That the relativeincrease in heart mass did not differ significantly betweenmale and female aortic-constricted rats is also consistentwith previous work in which heart mass was shown to besimilar in males and females early in the progression ofexperimental hypertensive heart disease [2].Gender, hypertrophy, and myocardial substrate utilizationGender-related differences in myocardial substrate utiliza-tion were observed in hypertrophied and non-hypertro-phied hearts before and after ischemia (Figure 2).Glycolysis was accelerated in hypertrophied hearts,regardless of sex, although the degree of acceleration wasless in females than in males (Figure 2A). This accelera-Representative immunoblots of key myocardial enzymes and proteins involved in glucose metabolism in non-hypertrophied (Control) nd hypertr phied (Hypertrophy) hearts from male (Male Path ogic Hypertrophy) and female (Femal  Pathologic Hy ertrophy) eartsFigu e 4Representative immunoblots of key myocardial enzymes and proteins involved in glucose metabolism in non-hypertrophied (Control) and hypertrophied (Hypertrophy) hearts from male (Male Pathologic Hypertrophy) and female (Female Pathologic Hypertrophy) hearts. Each lane represents a single heart. GLUT-4, glucose transport protein-4; HKII, hexokinase-II; PFK-1, phosphofructokinase-1; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; PDC E1α, pyruvate dehydrogeanse complex E1α subunit.Female Pathologic HypertrophyGlucosePyruvateMale Pathologic HypertrophyControl Hypertrophy Control HypertrophyGLUT4HKIIPFK1GAPDHEnolase-DEnolase-EPDC-E1DPage 8 of 13(page number not for citation purposes)was better maintained in female rats than in male rats, afinding that is entirely consistent with data from bothtion of glycolysis is consistent with previous data fromhypertrophied male rat hearts in vitro [19,23] and fromBMC Cardiovascular Disorders 2006, 6:8 http://www.biomedcentral.com/1471-2261/6/8hypertrophied dog [36] and rat [37] hearts in vivo. In malehypertrophied hearts, enhanced glycolytic rates were notaccompanied by changes in expression of key metabolicenzymes and proteins (Figure 4), a finding that contrastswith previous observations that activity of a number ofglycolytic enzymes is enhanced in hearts exposed to apressure overload, albeit in different species [38,39].Female hypertrophied hearts, on the other hand, demon-strated elevation of PFK-1, an enzyme having significantcontrol strength for glycolytic flux, but a reduction inexpression of another glycolyitc enzyme, enolase-β (Fig-ures 4 and 6), the latter finding having been described pre-viously in hypertrophied hearts from female rats [40].In general, oxidation of glucose (Figure 2B) and, to alesser extent, lactate (Figure 2D) was lower in femalehearts than in male hearts, except after ischemia, wherelactate oxidation rates in female hypertrophied heartswere higher than in corresponding male hearts. As withglycolysis, there was poor correspondence between meas-ured rates of flux through the PDC, an enzyme that con-tributes significantly to the control of myocardial glucoseand lactate oxidation, with its expression (Figure 4) andactivity. That the patterns of use differ between glucoseand lactate likely reflects the potential for fates of pyruvatederived from glucose and lactate to differ [41].Myocardial glycogen did not differ between hypertro-phied and non-hypertrophied hearts of either sex at theend of reperfusion, a finding in keeping with previousdata obtained in male rats [19]. That glycogen content waslower in female hearts compared to male hearts may be areflection of differences in the dynamic response of myo-cardial glycogen between males and females previouslyand hypertrophied hearts [28,43], gender-related differ-ences in glycogen metabolism could have contributed tothe functional differences observed in the current study.Fatty acid oxidation was depressed in male and femalehypertrophied hearts compared to corresponding non-hypertrophied hearts (Figure 2C), a finding consistentwith previous results in hypertrophied hearts from malerats [23,44,45]. Despite reductions in measured rates offatty acid oxidation, expression of MCAD and LCAD (Fig-ure 5), key enzymes in the mitochondrial β-oxidation spi-ral, was not significantly altered in this model of mildcompensated cardiac hypertrophy. The fall in fatty acidoxidation rates in female hearts after ischemia may berelated to lower contractile function, as the differencesdisappear when fatty acid oxidation rates are normalizedto work performed by the heart (data not shown). Nota-bly, the pattern of use of the other myocardial substratesis not altered significantly when cardiac workload isaccounted for. Taken together, hypertrophy-associatedchanges in substrate utilization rates and differences insubstrate utilization between male and female hypertro-phied hearts are not adequately accounted for by altera-tions in expression of metabolic enzymes and proteins,indicating that other factors, such as allosteric and/or cov-alent modification, translocation of glucose, fatty acid, orlactate transporters, substrate content, and product inhibi-tion, are likely responsible.Post-ischemic heart function and myocardial substrate utilizationThere is good evidence from experimental and clinicalstudies to indicate that the catabolic fate of glucose, andin particular the relative extent to which glucose is cat-Representative immunoblots of myocardial enzymes and proteins involved in fatty acid oxidation in non-hypertrophied (Con-trol) and hypertrophied (Hypertrophy) hearts from male (Mal  Pathologic Hypertrophy) and female (Female Pathologic Hyper-phy) heartsFigure 5Representative immunoblots of myocardial enzymes and proteins involved in fatty acid oxidation in non-hypertrophied (Con-trol) and hypertrophied (Hypertrophy) hearts from male (Male Pathologic Hypertrophy) and female (Female Pathologic Hyper-trophy) hearts. Each lane represents a different heart. MCAD, medium chain acyl-CoA dehydrogenase; LCAD, long-chain acyl-CoA dehydrogenase.Female Pathologic HypertrophyMale Pathologic HypertrophyControl Hypertrophy Control HypertrophyMCADLCADPage 9 of 13(page number not for citation purposes)reported [42]. As glycogen is known to contribute signifi-cantly to energy production in male non-hypertrophiedabolized oxidatively as compared to non-oxidatively, is animportant determinant of post-ischemic myocardial func-BMC Cardiovascular Disorders 2006, 6:8 http://www.biomedcentral.com/1471-2261/6/8tion in non-hypertrophied and hypertrophied hearts[19,20,22]. Substantial differences in non-oxidative glyc-olysis were observed among groups in the current study(Table 3). These differences were the result of gender-spe-cific alterations in glucose catabolism with differences inthe response of glycolysis to ischemia-reperfusionbetween male and female hearts being especially impor-tant because glucose oxidation rates were not similarlyaffected (Figure 2A and Table 3). Besides calculation fromand pyruvate by the heart, a parameter not measured inthe current experiments. Results from previous studiesindicate that an excellent correspondence exists betweenthese two parameters [46].When present, differences in non-oxidative glycolysiswere accompanied by differences in post-ischemic func-tion (Table 3 and Figure 1). In fact, we found a significantinverse relationship between non-oxidative glycolysis andDensitometric analysis of selected myocardial enzymes and proteins involved in myocardial glucose metabolism in non-hyper-trophied and hypertrophied hearts from male a d female ratsFigur  6Densitometric analysis of selected myocardial enzymes and proteins involved in myocardial glucose metabolism in non-hyper-trophied and hypertrophied hearts from male and female rats. (A) Enolase-α, (B) Enolase-β, (C) phosphofructokinase-1, and (D) pyruvate dehydrogeanse complex E1α subunit. White bar, male non-hypertrophied hearts; black bar, male hypertrophied hearts; light grey bar, female non-hypertrophied hearts; dark grey bar, female hypertrophied hearts. *, vs. sex-matched non-hypertrophied hearts (p < 0.05). $, vs. corresponding male hearts (p < 0.05). Values are expressed in arbitrary densitometry units, normalized to corresponding GAPDH densitometry units obtained from the same immunoblot. Numbers per group: 12 to 16 male non-hypertrophied hearts, 8 to 14 male hypertrophied hearts, and 6 to 8 female non-hypertrophied hearts, 6 to 8 female hypertrophied hearts. Values are mean ± SEM.B)A)D)C) *$ DensitometricUnits0. DensitometricUnits*$$ DensitometricUnits$Į$$Arbitrary DensitometricUnitsEnolase-ȕPFK-1Enolase-ĮPage 10 of 13(page number not for citation purposes)rates of glycolysis and glucose oxidation, non-oxidativeglycolysis can also be determined from release of lactaterecovery of contractile function after ischemia (Figure 3).The mechanism(s) by which non-oxidative glycolysisBMC Cardiovascular Disorders 2006, 6:8 http://www.biomedcentral.com/1471-2261/6/8influences contractile function during reperfusion is notyet fully known. However, based upon the different pro-ton stoichiometry of non-oxidative glucose catabolism ascompared to glucose oxidation, which indicates 2 molesof protons are produced per mole of glucose catabolizednon-oxidatively when the ATP formed is hydrolyzed[47,48], one possibility is that it is related to differences innet proton (H+) production arising from glucose catabo-lism [20]. Accelerated rates of H+ production have beenproposed to lead to increased calcium (Ca2+) overload asa result of successive trans-sarcolemmal H+/sodium (Na+)and Na+/Ca2+ exchange, which in turn increases the ener-getic cost associated with the maintenance of ion homeos-tasis and, in doing so, leads to reduced post-ischemiccontractile function and efficiency [20,49]. Future studies,in which pH and concentration of Na+ and Ca2+ in themyocardium of male and female hypertrophied and non-hypertrophied hearts are directly measured, will berequired to determine if this is the case.Other potential mechanismsIn addition to variability in non-oxidative glycolysis,other factors likely contribute to the differences in post-ischemic contractile function observed. Followingischemia, coronary flow was significantly lower in non-hypertrophied hearts from female rats than in corre-sponding hearts from male rats (Table 2), a finding thatmay account in part for the poor recovery of female com-pared to male non-hypertrophied hearts. Lower rates ofcoronary flow in hypertrophied hearts than in non-hyper-trophied hearts in both sexes may contribute to thereduced function in these hearts compared to correspond-ing non-hypertrophied hearts. Additionally, the genomicresponse to pressure overload is known to differ betweenhearts from males and females [50] with differentialexpression of a number of proteins relevant to functionaloutcome after ischemia, such as heat shock protein iso-forms [51], ATP sensitive potassium channels [52], andsarcoplasmic reticulum calcium ATPase [52], having beendescribed. The extent to which differences in expression ofsuch proteins contribute to the post-ischemic outcomes ofmale and female hypertrophied hearts remains to bedetermined.Methodological considerationsThe catabolism of endogenous substrates, such as glyco-gen and triglyceride, was not assessed in the current study.Given that endogenous substrates make significant contri-butions to overall energy production in the heart and thepotential for gender-related differences to exist, it will beimportant to directly measure catabolism of endogenoussubstrates in future studies to determine their potentialcontribution to the functional outcomes observed. In theting. A more comprehensive functional analysis using var-ying preload and afterload settings may have produceddifferent results in male and female hypertrophied andnon-hypertrophied hearts. Similarly, exposure to low-flow ischemia in contrast to no-flow ischemia may alsohave resulted in different post-ischemic outcomes thanthose in the current study. Future experiments will berequired to clarify these important issues.ConclusionGender does not significantly influence post-ischemicfunction of hypertrophied hearts, even though female sexis detrimental to post-ischemic function of non-hypertro-phied hearts. Differences in glucose catabolism may con-tribute to hypertrophy-induced and gender-relateddifferences in post-ischemic function.AbbreviationsKH, Krebs-Henseleit; GLUT-4, glucose transporter-4; HK,hexokinase; GAPDH, glyceraldehyde-3-phosphate dehy-drogenase; PDC, pyruvate dehydrogenase complex; PFK,phosphofructokinase; MCAD & LCAD, medium-chainand long-chain acyl-CoA dehydrogenases; ECL, enhancedchemiluminescent; ANOVA, analysis of variance; NMR,nuclear magnetic resonance.Competing interestsThe author(s) declare that they have no competing inter-ests.Authors' contributionsRS participated in writing the manuscript. RBW and HSLperfused the hearts and measured myocardial substrateutilization. HP and CA performed the immunoassays. AKand GAD and KMP provided antibodies and criticallyreviewed the manuscript. MFA is the senior author. 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Am J Physiol1988, 254(4 Pt 1):C560-563.Publish with BioMed Central   and  every scientist can read your work free of charge"BioMed Central will be the most significant development for disseminating the results of biomedical research in our lifetime."Sir Paul Nurse, Cancer Research UKYour research papers will be:available free of charge to the entire biomedical communitypeer reviewed and published immediately upon acceptancecited in PubMed and archived on PubMed Central BMC Cardiovascular Disorders 2006, 6:8 http://www.biomedcentral.com/1471-2261/6/843. Henning SL, Wambolt RB, Schonekess BO, Lopaschuk GD, Allard MF:Contribution of glycogen to aerobic myocardial glucose uti-lization.  Circulation 1996, 93(8):1549-1555.44. el Alaoui-Talibi Z, Landormy S, Loireau A, Moravec J: Fatty acid oxi-dation and mechanical performance of volume-overloadedrat hearts.  Am J Physiol 1992, 262(4 Pt 2):H1068-1074.45. 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Weinberg EO, Mirotsou M, Gannon J, Dzau VJ, Lee RT, Pratt RE: Sexdependence and temporal dependence of the left ventriculargenomic response to pressure overload.  Physiol Genomics 2003,12(2):113-127.51. Voss MR, Stallone JN, Li M, Cornelussen RN, Knuefermann P, Knowl-ton AA: Gender differences in the expression of heat shockproteins: the effect of estrogen.  Am J Physiol Heart Circ Physiol2003, 285(2):H687-692.52. Ranki HJ, Budas GR, Crawford RM, Jovanovic A: Gender-specificdifference in cardiac ATP-sensitive K(+) channels.  J Am CollCardiol 2001, 38(3):906-915.Pre-publication historyThe pre-publication history for this paper can be accessedhere:http://www.biomedcentral.com/1471-2261/6/8/prepubyours — you keep the copyrightSubmit your manuscript here:http://www.biomedcentral.com/info/publishing_adv.aspBioMedcentralPage 13 of 13(page number not for citation purposes)


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