Pharmaceutical Therapies for Necroptosis in Myocardial Ischemia–Reperfusion Injury

Abstract

Cardiovascular disease morbidity/mortality are increasing due to an aging population and the rising prevalence of diabetes and obesity. Therefore, innovative cardioprotective measures are required to reduce cardiovascular disease morbidity/mortality. The role of necroptosis in myocardial ischemia–reperfusion injury (MI–RI) is beyond doubt, but the molecular mechanisms of necroptosis remain incompletely elucidated. Growing evidence suggests that MI–RI frequently results from the superposition of multiple pathways, with autophagy, ferroptosis, and CypD-mediated mitochondrial damage, and necroptosis all contributing to MI–RI. Receptor-interacting protein kinases (RIPK1 and RIPK3) as well as mixed lineage kinase domain-like pseudokinase (MLKL) activation is accompanied by the activation of other signaling pathways, such as Ca2+/calmodulin-dependent protein kinase II (CaMKII), NF-κB, and JNK-Bnip3. These pathways participate in the pathological process of MI–RI. Recent studies have shown that inhibitors of necroptosis can reduce myocardial inflammation, infarct size, and restore cardiac function. In this review, we will summarize the molecular mechanisms of necroptosis, the links between necroptosis and other pathways, and current breakthroughs in pharmaceutical therapies for necroptosis.

The role of IFI16 in regulating PANoptosis and implication in heart diseases

“…The paper also discusses potential therapeutic strategies to inhibit necroptosis, which could be beneficial in treating MI by reducing cardiac cell death and inflammation. [ 117 ] It highlights how necroptosis contributes to the pathogenesis of MI by inducing cell death and inflammatory responses in the heart. The paper also reviews the signaling pathways involved in necroptosis and discusses the potential of targeting these pathways as a therapeutic approach in MI.…”

“…In animal models, pharmacological inhibitors that selectively target RIPK1, including necrostatin-1 have been demonstrated to decrease infarct size and myocardial cell death [ 115 , 116 ]. Since RIP1 is essential to the necroptosis pathway, blocking it has been shown to preserve the structural integrity of the heart and prevent the reactive fibrotic process from occurring after myocardial ischemia/reperfusion [ 117 ]. Furthermore, it has been suggested to employ pharmacological inhibitors that specifically target MLKL and RIPK3, two more elements of the necroptosis signaling cascade.…”

Is Intrinsic Cardioprotection a Laboratory Phenomenon or a Clinically Relevant Tool to Salvage the Failing Heart?

“…Thus, simulating the effect of RPC through pharmacological modulators of mPTP opening using drug cyclosporin A [144] appears to be a promising approach; this has already been applied in patients with AMI prior to angioplastic intervention [145,146]. It can be mentioned that such modulation of mPTP opening has also been suggested to underlie, in part, the cardioprotection of necrostatin-1, a drug that inhibits necroptosis, because its infarct sizereducing effects failed in cyclophilin-D-deficient mice (cyclophilin-D is a key component of mPTP) [147]. Although many questions are unresolved in this regard, including the precise role of mitochondria in necroptosis execution, these findings, as well as the data about the anti-necroptotic action of IPC [148], support the theory of cardioprotection by limiting this cell death due to mitochondria modulation.…”