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
• apoptóza * fyziologie   MeSH
• autofagie fyziologie   MeSH
• infarkt myokardu komplikace   patologie   MeSH
• nekroptóza fyziologie   MeSH
• potkani Sprague-Dawley MeSH
• potkani Wistar MeSH
• protein-serin-threoninkinasy interagující s receptory metabolismus   MeSH
• protein-serin-threoninkinasy metabolismus   MeSH
• signální transdukce MeSH
• srdeční komory patologie   MeSH
• srdeční selhání etiologie   metabolismus   patologie   MeSH
• velikost orgánu MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články 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
• apoptóza fyziologie   MeSH
• buněčná smrt fyziologie   MeSH
• infarkt myokardu metabolismus   MeSH
• kardiomyocyty metabolismus   MeSH
• krysa rodu rattus MeSH
• nekroptóza fyziologie   MeSH
• nekróza metabolismus   MeSH
• oxidační stres fyziologie   MeSH
• potkani Sprague-Dawley MeSH
• protein-serin-threoninkinasy interagující s receptory metabolismus   MeSH
• signální transdukce fyziologie   MeSH
• srdeční selhání metabolismus   MeSH
• upregulace fyziologie   MeSH
• zánět metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

• Klíčová slova
• etóza, netóza,
• MeSH
• apoptóza fyziologie   MeSH
• autofagie fyziologie   MeSH
• buněčná smrt * fyziologie   MeSH
• kaspasy MeSH
• lidé MeSH
• nekroptóza fyziologie   MeSH
• nekróza MeSH
• pyroptóza fyziologie   MeSH
• regulovaná buněčná smrt fyziologie   MeSH
• zánět patofyziologie   patologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• přehledy MeSH