Evidence of necroptosis in hearts subjected to various forms of ischemic insults

Abstract

Long-lasting ischemia can result in cell loss; however, repeated episodes of brief ischemia increase the resistance of the heart against deleterious effects of subsequent prolonged ischemic insult and promote cell survival. Traditionally, it is believed that the supply of blood to the ischemic heart is associated with release of cytokines, activation of inflammatory response, and induction of necrotic cell death. In the past few years, this paradigm of passive necrosis as an uncontrolled cell death has been re-examined and the existence of a strictly regulated form of necrotic cell death, necroptosis, has been documented. This controlled cell death modality, resembling all morphological features of necrosis, has been investigated in different types of ischemia-associated heart injuries. The process of necroptosis has been found to be dependent on the activation of RIP1-RIP3-MLKL axis, which induces changes leading to the rupture of cell membrane. This pathway is activated by TNF-α, which has also been implicated in the cardioprotective signaling pathway of ischemic preconditioning. Thus, this review is intended to describe the TNF-α-mediated signaling leading to either cell survival or necroptotic cell death. In addition, some experimental data suggesting a link between heart dysfunction and the cellular loss due to necroptosis are discussed in various conditions of myocardial ischemia.

Bisphenol A induces coronary endothelial cell necroptosis by activating RIP3/CamKII dependent pathway

“…Our data showed increased cell death in hearts from BPA treated mice, especially in the areas containing blood vessels, in the absence of increased apoptotic markers. Necroptosis is a newly discovered pathway of programmed cell death with an essential role in human ischemic injury 72 . RIP 3 is a critical determinant in the necroptotic pathway and is expressed in the myocardium 73 .…”

Determination of Novel Highly Effective Necrostatin Nec-1s in Rat Plasma by High Performance Liquid Chromatography Hyphenated with Quadrupole-Time-of-Flight Mass Spectrometry

“…Inhibition of receptor interacting protein 1 (RIP1) by a drug class referred to as the necrostatins has been shown to retard necroptosis, a form of programmed necrotic-like cell death which has been suggested to underlie pathophysiology of various diseases, including neurodegenerative diseases [ 1 ], acute inflammatory conditions [ 2 ], malignancies [ 3 ] and cardiovascular diseases associated with ischemia (reviewed by [ 4 , 5 ]). Necrostatin-1 (Nec-1, 5-(indol-3-ylmethyl)(2-thio-3-methyl)hydantoin), the first discovered necrostatin [ 6 ], which acts as an allosteric inhibitor of kinase domain of RIP1, has been widely used in some of these studies [ 4 , 7 , 8 ].…”

Disease-modifying antirheumatic drugs and remote ischemic postconditioning ameliorate the myocardial injury in rats under cerebral stroke

“…We found that necrosis in the myocardium and cardiac MDA levels were significantly decreased after postconditioning as compared to the control group. Prolonged ischemia can cause cell loss, however, recurrent short ischemia episodes in short terms in the distal skeletal muscle may have revealed an increase in the resistance to the detrimental effects of the long-term ischemic condition in the heart (17), and thus improved the survival of the cells in the current study.…”

“…The process of necrosis was found to be dependent on the activation of the receptor-interacting protein (RIP)1, RIP3, and a mixed-lineage kinase domain-like protein axis. This pathway is activated by TNF-α, which is also present in the cardioprotective signaling pathway of ischemic pre-conditioning (17). The association between TNF inhibitors and myocarfial infarction has been investigated previously and it has been demonstrated that TNF inhibitors offer a reduced MI risk, while some other studies found the risk to be similar when they were compared to DMARDs (6).…”