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UBC Theses and Dissertations

Role of the RhoA/ROCK pathway in hypertension associated with diabetes Rao, Milly Yushu


Hypertension is the most common cardiovascular complication associated with diabetes mellitus. The RhoA/ROCK pathway has been implicated in the regulation of vascular smooth muscle contractile responses associated with hypertension and diabetes. Here we wished to determine the role of the RhoA/ROCK pathway in vascular smooth muscle contractile responses in different types of diabetic models and its contribution to diabetes-associated hypertension. Our results suggest that the involvement of ROCK may be more important in U-46619- than in PE-induced contractile responses in endothelium denuded mesenteric resistance arteries from control rats. On the other hand, as found in our previous work and other reports, PE-induced contractile responses were attenuated by inhibition of ROCK in rat superior mesenteric arteries, suggesting that ROCK is likely to play an essential role in PE-induced contraction in superior mesenteric arteries. Blood pressure in GK rats was normalized by one-week treatment with fasudil, a known ROCK inhibitor, suggesting that the elevated blood pressure in GK rats may be due to enhanced ROCK pathway. However, agonist-induced contractile responses in GK mesenteric resistance arteries were not augmented compared to control arteries, and moreover, expression of ROCK/RhoA as well as activity of ROCK were similar between control and GK arteries. The specific causes of the discrepancy remain unknown. In the presence of L-NAME, ROCK inhibitor significantly attenuated contraction induced by PE or U-46619 in mesenteric resistance arteries from GK rats, suggesting that agonist-induced contractile responses in mesenteric resistance arteries from GK rats were likely to be ROCK-mediated. This was further supported by Western blotting results, in that phosphorylation of MYPT was significantly increased by U-46619. Interestingly, U-46619-induced contraction in mesenteric resistance arteries from control rats was no longer sensitive to inhibition of ROCK in the presence of L-NAME, although the reasons were unclear. In conclusion, results from the GK rat study do not support the hypothesis that activation of the RhoA/ROCK pathway contributes to the development of diabetes-associated hypertension in GK rats by enhancing vascular smooth muscle contractile responses. To further investigate this study, a more ROCK selective ROCK inhibitor is needed.

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