Nicorandil regulates the macrophage skewing and ameliorates myofibroblasts by inhibition of RhoA/Rho‐kinase signalling in infarcted rats

Abstract

We have demonstrated that ATP‐sensitive potassium (KATP) channel agonists attenuated fibrosis; however, the mechanism remained unclear. Since RhoA has been identified as a mediator of cardiac fibrosis, we sought to determine whether the anti‐fibrotic effects of KATP channel agonists were mediated via regulating macrophage phenotype and fibroblast differentiation by a RhoA/RhoA‐kinase‐dependent pathway. Wistar male rats after induction of myocardial infarction were randomized to either vehicle, nicorandil, an antagonist of KATP channel glibenclamide, an antagonist of ROCK fasudil, or a combination of nicorandil and glibenclamide or fasudil and glibenclamide starting 24 hrs after infarction. There were similar infarct sizes among the infarcted groups. At day 3 after infarction, post‐infarction was associated with increased RhoA/ROCK activation, which can be inhibited by administering nicorandil. Nicorandil significantly increased myocardial IL‐10 levels and the percentage of regulatory M2 macrophages assessed by immunohistochemical staining, Western blot, and RT‐PCR compared with vehicle. An IL‐10 receptor antibody increased myofibroblast infiltration compared with nicorandil alone. At day 28 after infarction, nicorandil was associated with attenuated cardiac fibrosis. These effects of nicorandil were functionally translated in improved echocardiographically derived cardiac performance. Fasudil showed similarly increased expression of M2 macrophages as nicorandil. The beneficial effects of nicorandil on fibroblast differentiation were blocked by adding glibenclamide. However, glibenclamide cannot abolish the attenuated fibrosis of fasudil, implying that RhoA/RhoA‐kinase is a downstream effector of KATP channel activation. Nicorandil polarized macrophages into M2 phenotype by inhibiting RhoA/RhoA‐kinase pathway, which leads to attenuated myofibroblast‐induced cardiac fibrosis after myocardial infarction.

Pre-treatment With Fasudil Prevents Neomycin-Induced Hair Cell Damage by Reducing the Accumulation of Reactive Oxygen Species

“…The different forms of Rho can further trigger downstream kinase cascades, thereby exerting multiple biological effects (Surma et al, 2011; Antoniu, 2012; Amin et al, 2013). Fasudil can also attenuate cardiac fibrosis by inhibiting the RhoA/RhoA-kinase pathway (Lee et al, 2017).…”

“…Fasudil has significant neuroprotective and therapeutic effects in the treatment of ischemic cerebrovascular disease (Rikitake et al, 2005), and it can reduce the number of macrophages and neutrophils in alveolar lavage fluid by inhibiting the Rho/Rock signaling pathway (Galiè et al, 2005; Doe et al, 2009; Yasuda et al, 2011; Jiang et al, 2012). Inhibition of the Rho/Rock signaling pathway can reduce oxidative stress and increase sulfur dioxygenase activity (Lee et al, 2017). Rho-kinase (ROCK) has been reported to be involved in many cellular functions such as cell contraction, adhesion, and migration (Ohsawa et al, 2016).…”

Impact of statins on cellular respiration and de‐differentiation of myofibroblasts in human failing hearts

“…Co‐incubation of statins with glibenclamide, a K ATP channel inhibitor, attenuated the statin‐induced myofibroblast de‐differentiation, suggesting that activation of K ATP channels by increased ADP/ATP ratio, caused by statins, may play a role in statin‐induced myofibroblast de‐differentiation. In conformity, recently, nicorandil, a K ATP channel agonist, was demonstrated to attenuate myocardial fibrosis and improve cardiac function after myocardial infarction in rats …”

The impact of oral nicorandil pre-treatment on ST resolution and clinical outcome of patients with acute ST-segment elevation myocardial infarction undergoing primary coronary angioplasty: A randomized placebo controlled trial

“…26 Nicorandil also shifts the macrophage phenotype and leads to less myofibroblast differentiation through the inhibition of RhoA/RhoA-kinase-dependent pathway. 27 Myofibroblast is suggested to be involved in the progression of left ventricular remodeling and arrhythmogenic activity. 28,29 This suggestion, however, is only a hypothesisgenerating interpretation and needs further larger human studies for confirmation.…”