3.1 Necroptosis in Cardiac fibrosis
Cardiac fibrosis is featured by excessive accumulation of ECM proteins in the myocardium, distorts the architecture of the myocardium, and contributes to arrhythmia and cardiac dysfunction in many cardiac pathophysiologic situations involing myocardial infarct, I/R injury and cardiac failure (Li, Zhao and Kong 2018). Recent research shows that necroptosis plays an important role in these cardiac diseases. Literatures show that targeting necroptosis by RIPK3 gene knockout in mice can reduce susceptibility of myocardial failure triggered by I/R or doxorubicin (a cardiotoxic chemotherapeutic agent) (Zhang et al. 2016b, Luedde et al. 2014). Experiments with isolated cardiomyocytes found that activated RIPK3 in myocardium seems to trigger a CaMKII-reliant signal pathway, outcomes of mitochondrial permeability transition and consequent necrosis (Zhang et al. 2016b). Another research found that S. pneumoniae  can intrudes the myocardium and generates cardiac damage with necroptosis and apoptosis, in a nonhuman primate model of severe pneumonia. Once cardiomyocytes die, heart tissue is replaced with myofibroblasts that produce an ECM that is rich in collagen and leads to scar formation (Souders, Bowers and Baudino 2009). Necrostatin-1 (Nec-1), a small molecule inhibitor targeting RIPK1 of necroptosis, can keep off infaust heart remodeling after myocardial I/R in vivo. This protective effect of Nec-1 on heart features the value of necroptosis in myocardial ischemia disease (Oerlemans et al. 2012). Besides RIPK1, RIPK3 also shows an important regulatory role in myocardial injury. Experiment study shows that the obviously increased expression of RIPK3 in mice hearts suffered to I/R injury was positively correlated to the infarct area enlargement, cardiac insufficiency and expansive cardiomyocytes necroptosis. Further mechanistic studies indicated that gene knockout of RIPK3 eliminated the endoplasmic reticulum stress and prevent the ([Ca2+]c) overload-XO-ROS-mPTP pathways, outcomes to a pro-survival state by inhibition of cardiomyocytes necroptosis in cardiac IR injury (Zhu et al. 2018b). Another interesting research found that conditional gene knockout of COP9 signalosome complex subunit 8 in mice cardiomyocytes appears plenty of myocardial cell necroptosis followed by acute heart failure and premature death. Cardiac Cops8/COP9 signalosome obstacle shows RIPK1-RIPK3 dependent in myocardial cell in mice, Thus, researchers speculated that COP9 signalosome plays an important part in restraining myocardial cell necroptosis (Xiao et al. 2020). The above research shows that Inhibition of necroptosis of cardiomyocytes may improve cardiac fibrosis and further to protect heart function.