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The role of Rho kinase 2 in the development of ischemia/reperfusion injury in normal and diabetic hearts Garcia Patino, Marysol


During myocardial infarction, the heart enters into an ischemic state that, if untreated, leads to cell death. To avoid this, reperfusion must be instituted. However, this causes a type of cardiac damage known as myocardial ischemia-reperfusion (I/R) injury. Concomitant diseases such as diabetes not only increase the risk of myocardial infarction, but also intensify susceptibility to I/R injury. Over-activation of Rho kinase (ROCK) has been reported to contribute to I/R injury; however, it is unknown whether ROCK1, ROCK2 or both isoforms, is/are responsible for this effect. Furthermore, it has not been determined if the cardioprotective activity of ROCK inhibition is maintained under diabetic conditions. Here, we evaluated the contribution of ROCK2 to myocardial I/R injury, as well as its role during diabetes. The induction of I/R injury impaired cardiac function in wild-type (WT) but not heterozygous ROCK2-knockdown (ROCK2+/-) mice. Infarct size was also lower in ROCK2+/- mice than in their WT counterparts, while an I/R-induced increase in ROCK activity was detected only in WT hearts. The cardioprotection observed in ROCK2+/- mice was associated with increased Akt and GSK-3β phosphorylation and a reduction of I/R-induced cytokine production. Compared to their ROCK2-expressing counterparts, cardiac-specific ROCK2 knockout (cROCK2-/-) mice subjected to I/R also had a smaller infarct size, suggesting that the deleterious effects of I/R are at least partially regulated by cardiomyocyte ROCK2. However, the induction of diabetes by streptozotocin treatment abrogated the protective effect of cardiomyocyte-specific ROCK2 deletion. ROCK activity was comparable in control and diabetic post-I/R cROCK2-/- hearts, but the increase in Akt and GSK-3β phosphorylation was no longer detected under diabetic conditions. Furthermore, cytokine production in non-diabetic cROCK2-/- mice was higher than in their ROCK2 expressing counterparts, and this was normalized in diabetic conditions. Overall, these results show that ROCK2 plays a significant role in the development of myocardial I/R injury, and that its inhibition is associated with activation of the pro-survival RISK-pathway. Moreover, the cardioprotection obtained by the cardiac-specific deletion of this isoform suggests that I/R-induced ROCK2 activation takes place in the cardiomyocyte. However, this cardioprotective effect is lost during diabetes, possibly due to impaired Akt and GSK-3β phosphorylation.

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