Involvement of RhoA/ROCK in myocardial fibrosis in a rat model of type 2 diabetes

Abstract

Aim: To investigate whether activation of RhoA/Rho kinase (ROCK) is involved in myocardial fibrosis in diabetic hearts. Methods: A rat model of type 2 diabetes was established using high fat diet combined with streptozotocin (30 mg/kg, ip). Animals were randomly divided into 3 groups: control rats, untreated diabetic rats that received vehicle and treated diabetic rats that received Rhokinase inhibitor fasudil hydrochloride hydrate (10 mg·kg -1 ·d -1 , ip, for 14 weeks). Cardiac contractile function was evaluated in vivo. The morphological features of cardiac fibrosis were observed using immunohistochemistry and TEM. The mRNA expression of JNK, TGFβ1, type-I, and type-III procollagen was assessed with RT-PCR. The phosphorylation of MYPT1, JNK and Smad2/3, as well as the protein levels of TGFβ1 and c-Jun, were evaluated using Western blotting. Results: In untreated diabetic rats, myocardial fibrosis was developed and the heart contractility was significantly reduced as compared to the control rats. In the hearts of untreated diabetic rats, the mRNA expression level and activity of JNK were upregulated; the expression of TGFβ1 and phosphorylation of Smad2/3 were increased. In the hearts of treated diabetic rat, activation of JNK and TGFβ/Smad was significantly decreased, myocardial fibrosis was reduced, and cardiac contractile function improved. Conclusion: The data suggest that fasudil hydrochloride hydrate ameliorates myocardial fibrosis in rats with type 2 diabetes at least in part through inhibiting the JNK and TGFβ/Smad pathways. Inhibition of RhoA/ROCK may be a novel therapeutic target for prevention of diabetic cardiomyopathy.

Hypoxia Suppresses TGF-B1-Induced Cardiac Myocyte Myofibroblast Transformation by Inhibiting Smad2/3 and Rhoa Signaling Pathways

“…TGF-β can rapidly activate RhoA-dependent signaling pathways to induce EMT [18]. It has been reported that RhoA/ROCK involvement in remodeling of the myocardial matrix in diabetic rats may be associated with activation of the TGF-β/Smad pathway [35]. The changes in p-RhoA expression are similar to our observation of Smads under hypoxia and TGF-β1 co-treatment.…”

Contribution of Rho kinase to blood pressure elevation and vasoconstrictor responsiveness in type 2 diabetic Goto–Kakizaki rats

“…In a previous investigation from this laboratory, we demonstrated that the pathway is overactive in hearts from rats with chronic streptozotocin (STZ)-induced diabetes, and that acute inhibition of ROCK improves cardiac function in these animals both in vivo and in isolated working hearts [6], suggesting that the RhoA/ ROCK pathway also plays a critical role in the development of diabetic cardiomyopathy. This is supported by a recent study that showed that chronic inhibition of ROCK produced a sustained improvement in contractile function of hearts from diabetic rats [7].…”

Is It Possible to Recover Erectile Function Spontaneously after Cavernous Nerve Injury? Time-Dependent Structural and Functional Changes in Corpus Cavernosum Following Cavernous Nerve Injury in Rats

“…Furthermore, many studies have shown that the RhoA/Rho-associated kinase pathway plays an important role in tissue fibrosis and that Rho-kinase inhibition prevents and ameliorates tissue fibrosis. 11,[20][21][22][23][24][25] Therefore, our results may raise the possibility of targeting the RhoA/ROCK pathway to prevent corporal fibrosis and preserve the corpus cavernosum in the early period after partial or incomplete nerve injury. One of the novel findings of this study was that the erectile response had not spontaneously normalized at 4 or 12 weeks after CN injury, despite recovery of Akt and eNOS phosphorylation.…”