OBJECTIVE: The purpose of the present study was to determine whether increased activation of the RhoA/Rho-kinase (ROCK) pathway occurs in diabetic cardiomyopathy and whether acute inhibition of this pathway improves contractile function of the diabetic heart. METHODS: Male Wistar rats were made diabetic with streptozotocin. Twelve to fourteen weeks later, the effects of acute administration of the ROCK inhibitors Y-27632 and H-1152 on cardiac contractile function were measured both in vitro, in isolated working hearts, and in vivo, using echocardiography. Changes in the expression and activity of RhoA, and the effect of ROCK inhibition on changes in the phosphorylation of the downstream target of ROCK, LIM kinase 2, and on actin polymerization in diabetic hearts were also determined. RESULTS: Perfusion of isolated working hearts from diabetic rats with Y-27632 or H-1152 acutely improved left ventricle developed pressure and the rates of contraction and relaxation. Acute administration of H-1152 also significantly improved the percent fraction shortening, an index of left ventricle contractility, in vivo in diabetic rats. The expression and activity of RhoA in cardiomyocytes from diabetic rats were significantly increased, as was the phosphorylation of LIM kinase 2. This was associated with an increase in actin polymerization (the F-actin to G-actin ratio). Both the increase in LIM kinase 2 phosphorylation and actin polymerization were attenuated by ROCK inhibition. CONCLUSIONS: These data suggest that activation of the RhoA/ROCK signaling pathway plays a critical role in the development of diabetic cardiomyopathy, and that ROCK is an excellent therapeutic target in the treatment of this condition.
OBJECTIVE: The purpose of the present study was to determine whether increased activation of the RhoA/Rho-kinase (ROCK) pathway occurs in diabetic cardiomyopathy and whether acute inhibition of this pathway improves contractile function of the diabetic heart. METHODS: Male Wistar rats were made diabetic with streptozotocin. Twelve to fourteen weeks later, the effects of acute administration of the ROCK inhibitors Y-27632 and H-1152 on cardiac contractile function were measured both in vitro, in isolated working hearts, and in vivo, using echocardiography. Changes in the expression and activity of RhoA, and the effect of ROCK inhibition on changes in the phosphorylation of the downstream target of ROCK, LIM kinase 2, and on actin polymerization in diabetic hearts were also determined. RESULTS: Perfusion of isolated working hearts from diabeticrats with Y-27632 or H-1152 acutely improved left ventricle developed pressure and the rates of contraction and relaxation. Acute administration of H-1152 also significantly improved the percent fraction shortening, an index of left ventricle contractility, in vivo in diabeticrats. The expression and activity of RhoA in cardiomyocytes from diabeticrats were significantly increased, as was the phosphorylation of LIM kinase 2. This was associated with an increase in actin polymerization (the F-actin to G-actin ratio). Both the increase in LIM kinase 2 phosphorylation and actin polymerization were attenuated by ROCK inhibition. CONCLUSIONS: These data suggest that activation of the RhoA/ROCK signaling pathway plays a critical role in the development of diabetic cardiomyopathy, and that ROCK is an excellent therapeutic target in the treatment of this condition.
Authors: Tran Thi Hien; Karolina M Turczyńska; Diana Dahan; Mari Ekman; Mario Grossi; Johan Sjögren; Johan Nilsson; Thomas Braun; Thomas Boettger; Eliana Garcia-Vaz; Karin Stenkula; Karl Swärd; Maria F Gomez; Sebastian Albinsson Journal: J Biol Chem Date: 2015-12-18 Impact factor: 5.157
Authors: Wai Ho Tang; Wing Tim Cheng; Gennadi M Kravtsov; Xiao Yong Tong; Xiu Yun Hou; Sookja K Chung; Stephen Sum Man Chung Journal: Am J Physiol Cell Physiol Date: 2010-06-23 Impact factor: 4.249
Authors: Khaled S Abd-Elrahman; Olaia Colinas; Emma J Walsh; Hai-Lei Zhu; Christine M Campbell; Michael P Walsh; William C Cole Journal: J Cereb Blood Flow Metab Date: 2015-12-31 Impact factor: 6.200
Authors: Jessica Lauriol; Kimberly Keith; Fabrice Jaffré; Anthony Couvillon; Abdel Saci; Sanjeewa A Goonasekera; Jason R McCarthy; Chase W Kessinger; Jianxun Wang; Qingen Ke; Peter M Kang; Jeffery D Molkentin; Christopher Carpenter; Maria I Kontaridis Journal: Sci Signal Date: 2014-10-21 Impact factor: 8.192