While necroptosis has been shown to contribute to the pathogenesis of post-infarction heart failure (HF), the role of autophagy remains unclear. Likewise, linkage between these two cell death modalities has not been sufficiently investigated. HF was induced by 60-min left coronary occlusion in adult Wistar rats and heart function was assessed 6 weeks later followed by immunoblotting analysis of necroptotic and autophagic proteins in both the left (LV) and right ventricle (RV). HF had no effect on RIP1 and RIP3 expression. PhosphoSer229-RIP3, acting as a pro-necroptotic signal, was increased in LV while deceased in RV of failing hearts. Total MLKL was elevated in RV only. Decrease in pSer555-ULK1, increase in pSer473-Akt and no significant elevation in beclin-1 and LC3-II/I ratio indicated rather a lowered rate of autophagy in LV. No beclin-1 upregulation and decreased LC3 processing also suggested the inhibition of both autophagosome formation and maturation in RV of failing hearts. In contrast, p89 PARP1 fragment, a marker of executed apoptosis, was increased in RV only. This is the first study showing a different signaling in ventricles of the late phase of post-infarction HF, highlighting necroptosis itself rather than its linkage with autophagy in LV, and apoptosis in RV.

• MeSH
• Apoptosis * physiology   MeSH
• Autophagy physiology   MeSH
• Myocardial Infarction complications   pathology   MeSH
• Necroptosis physiology   MeSH
• Rats, Sprague-Dawley MeSH
• Rats, Wistar MeSH
• Receptor-Interacting Protein Serine-Threonine Kinases metabolism   MeSH
• Protein Serine-Threonine Kinases metabolism   MeSH
• Signal Transduction MeSH
• Heart Ventricles pathology   MeSH
• Heart Failure etiology   metabolism   pathology   MeSH
• Organ Size MeSH
• Animals MeSH
• Check Tag
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

Necroptosis has been recognized in heart failure (HF). In this study, we investigated detailed necroptotic signalling in infarcted and non-infarcted areas separately and its mechanistic link with main features of HF. Post-infarction HF in rats was induced by left coronary occlusion (60 minutes) followed by 42-day reperfusion. Heart function was assessed echocardiographically. Molecular signalling and proposed mechanisms (oxidative stress, collagen deposition and inflammation) were investigated in whole hearts and in subcellular fractions when appropriate. In post-infarction failing hearts, TNF and pSer229-RIP3 levels were comparably increased in both infarcted and non-infarcted areas. Its cytotoxic downstream molecule p-MLKL, indicating necroptosis execution, was detected in infarcted area. In non-infarcted area, despite increased pSer229-RIP3, p-MLKL was present in neither whole cells nor the cell membrane known to be associated with necroptosis execution. Likewise, increased membrane lipoperoxidation and NOX2 levels unlikely promoted pro-necroptotic environment in non-infarcted area. Collagen deposition and the inflammatory csp-1-IL-1β axis were active in both areas of failing hearts, while being more pronounced in infarcted tissue. Although apoptotic proteins were differently expressed in infarcted and non-infarcted tissue, apoptosis was found to play an insignificant role. p-MLKL-driven necroptosis and inflammation while inflammation only (without necroptotic cell death) seem to underlie fibrotic healing and progressive injury in infarcted and non-infarcted areas of failing hearts, respectively. Upregulation of pSer229-RIP3 in both HF areas suggests that this kinase, associated with both necroptosis and inflammation, is likely to play a dual role in HF progression.

• MeSH
• Apoptosis physiology   MeSH
• Cell Death physiology   MeSH
• Myocardial Infarction metabolism   MeSH
• Myocytes, Cardiac metabolism   MeSH
• Rats MeSH
• Necroptosis physiology   MeSH
• Necrosis metabolism   MeSH
• Oxidative Stress physiology   MeSH
• Rats, Sprague-Dawley MeSH
• Receptor-Interacting Protein Serine-Threonine Kinases metabolism   MeSH
• Signal Transduction physiology   MeSH
• Heart Failure metabolism   MeSH
• Up-Regulation physiology   MeSH
• Inflammation metabolism   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

• Keywords
• etóza, netóza,
• MeSH
• Apoptosis physiology   MeSH
• Autophagy physiology   MeSH
• Cell Death * physiology   MeSH
• Caspases MeSH
• Humans MeSH
• Necroptosis physiology   MeSH
• Necrosis MeSH
• Pyroptosis physiology   MeSH
• Regulated Cell Death physiology   MeSH
• Inflammation physiopathology   pathology   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Review MeSH