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.