Necroptosis in cardiovascular disease - a new therapeutic target

Abstract

Contrary to the apoptosis-necrosis binary view of cell death, recent experimental evidence demonstrates that several forms of necrosis, represented by necroptosis, are regulated or programmed in nature. Multiple death stimuli known to be associated with cardiovascular disease are capable of causing either apoptosis or necroptosis. Whether a cell dies from apoptosis or necroptosis has distinct consequences on inflammation. It is known that apoptosis, a non-lytic form of death mediated by the caspase family of proteases, does not generally evoke an immune response. Necroptosis, on the other hand, is a lytic form of cell death. Due to the rapid loss of plasma membrane integrity, cells dying from necroptosis release proinflammatory intracellular contents and subsequently cause inflammation. Our review delineates various genetic and biochemical evidence that demonstrates a compelling role of necroptosis in the pathogenesis and/or progression of cardiovascular disease including myocardial infarction, atherosclerosis, and aortic aneurysm. Through recent studies of necroptosis in cardiovascular diseases, we attempt to discuss the role of necroptosis in vascular inflammation as well as the potential of necroptosis inhibitors in future clinical management of cardiovascular events. Inhibiting necroptosis in the vasculature has an overall protective role and necroptosis may represent a new therapeutic target to prevent the development and progression of cardiovascular diseases.

ZYZ-803 Mitigates Endoplasmic Reticulum Stress-Related Necroptosis after Acute Myocardial Infarction through Downregulating the RIP3-CaMKII Signaling Pathway

“…This strategy exploits the use of drug entities that protect the heart from stress-induced injury, to prevent cell necrosis and to promote recovery. Cardiac necroptosis plays a pivotal pathological role in myocardial ischemic injury and has been seen as a new therapeutic target for ischemic heart injury [37, 38]. Meanwhile, H 2 S and NO are recognized as gasotransmitters with widely pathophysiological roles in cardiovascular diseases, and both of them are dysregulated in the pathogenesis of myocardial ischemic injury, which can be rescued by H 2 S and/or NO donors through different mechanisms including complex interplays of H 2 S and NO [30, 39, 40].…”

Necroptosis: a crucial pathogenic mediator of human disease

“…Necroptosis-associated proteins have been implicated as therapeutic targets in various cardiovascular diseases, including heart failure, myocardial injury, aortic aneurysm, ischemic neural injury, and stroke (7,(111)(112)(113). In a mouse model of atherosclerosis (LDL receptor deficiency), Ripk3 and Ldlr double-knockout mice displayed reduced atherosclerotic lesions during the late state of disease progression and evidence of reduced macrophage necrosis but not apoptosis (114).…”

Necroptosis in the Pathophysiology of Disease

“…Therefore, cells undergoing necroptosis are indistinguishable from those undergoing necrosis, using standard histologic techniques. Although apoptosis and necroptosis frequently have common triggers, 3 the intracellular signaling pathways leading to the execution of apoptosis and necroptosis differ. In the same way that caspases are key intracellular mediators of apoptosis, receptor-interacting protein kinases (RIPKs) are essential mediators in necroptosis.…”