Abstract
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.
Highlights
Understanding the mechanisms of cell death in heart failure (HF) after myocardial infarction (MI) is of great clinical importance, since the extent of cellular loss significantly determines the degree of cardiac injury, contractile dysfunction, adverse remodeling and patient prognosis [1,2,3]
Data obtained from left ventricle (LV) catheterization of post-MI rats showed impaired cardiac systolic and diastolic function indicating the development of HF: developed pressure and rates of pressure development and decline were significantly reduced, and end-diastolic pressure was increased compared to sham procedure (Sham) group
Autophagy-associated cell death does not seem to have a substantial effect in promoting the functional deterioration of the LV, as we have found no evidence of its activation under these settings (Figure 6)
Summary
Understanding the mechanisms of cell death in heart failure (HF) after myocardial infarction (MI) is of great clinical importance, since the extent of cellular loss significantly determines the degree of cardiac injury, contractile dysfunction, adverse remodeling and patient prognosis [1,2,3]. MLKL aggregates into a cytotoxic homo/hetero-amyloid structure [12,13,14,15] and translocates into the plasma membrane causing the alterations in ion homeostasis, membrane disruption, and cell lysis [13,16,17,18]. MLKL has been reported to facilitate the proteases-mediated degradation of plasma membrane structures, and promote membrane oxidative stress via NOX1 activation and NLRP3-mediated inflammation [19]. These features have highlighted the role of MLKL in the execution of necroptosis and it is considered to be a terminal necroptotic protein. A role of RIP1 in the activation of necroptosis has been challenged and RIP1-independent mechanisms of the RIP3-MLKL interplay in necroptosis execution have been indicated [19,20]
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