Autophagy and Inflammasome Activation in Dilated Cardiomyopathy

Abstract

Background: The clinical outcome of patients affected by dilated cardiomyopathy (DCM) is heterogeneous, since its pathophysiology is only partially understood. Interleukin 1β levels could predict the mortality and necessity of cardiac transplantation of DCM patients. Objective: To investigate mechanisms triggering sterile inflammation in dilated cardiomyopathy (DCM). Methods: Hearts explanted from 62 DCM patients were compared with 30 controls, employing immunohistochemistry, cellular and molecular biology, as well as metabolomics studies. Results: Although misfolded protein accumulation and aggresome formation characterize DCM hearts, aggresomes failed to trigger the autophagy lysosomal pathway (ALP), with consequent accumulation of both p62SQSTM1 and dysfunctional mitochondria. In line, DCM hearts are characterized by accumulation of lipoperoxidation products and activation of both redox responsive pathways and inflammasome. Consistently with the fact that mTOR signaling may impair ALP, we observed, an increase in DCM activation, together with a reduction in the nuclear localization of Transcription Factor EB -TFEB- (a master regulator of lysosomal biogenesis). These alterations were coupled with metabolomic alterations, including accumulation of branched chain amino acids (BCAAs), known mTOR activators. Consistently, reduced levels of PP2Cm, a phosphatase that regulates the key catabolic step of BCAAs, coupled with increased levels of miR-22, a regulator of PP2Cm levels that triggers senescence, characterize DCM hearts. The same molecular defects were present in clinically relevant cells isolated from DCM hearts, but they could be reverted by downregulating miR-22. Conclusion: We identified, in human DCM, a complex series of events whose key players are miR-22, PP2Cm, BCAA, mTOR, and ALP, linking loss of proteostasis with inflammasome activation. These potential therapeutic targets deserve to be further investigated.

Transfer of a human gene variant associated with exceptional longevity improves cardiac function in obese type 2 diabetic mice through induction of the SDF‐1/CXCR4 signalling pathway

“…A line crossing the centre of nuclei was drawn and the length of the segment crossing the opposite intercalated discs was then measured, in analogy to what has been described in Vliegen et al, 14 and published by us recently. 15 Vascular density was assessed by counting capillaries in at least 10 fields (200x magnification). Final data were expressed as the number of capillaries per mm 2 .…”

Longevity genes, cardiac ageing, and the pathogenesis of cardiomyopathy: implications for understanding the effects of current and future treatments for heart failure

“…Diseases that lead to heart failure (as well as the heart failure state itself) mimic the ageing process, in that they are characterized by an increase in oxidative and endoplasmic reticulum stress, which is exacerbated by a striking impairment in the capacity of the heart to stimulate autophagy. Autophagic flux of cardiomyocytes is markedly impaired in cardiomyocytes derived from injured or failing hearts 147–149 ; in return, pharmacological stimulation of autophagic flux can directly ameliorate oxidative stress and organellar dysfunction, thereby preventing or reversing cardiomyocyte dysfunction and mitigating the development of cardiomyopathy. 150–152 This deficiency in autophagic capacity in heart failure is related to the simultaneous impairment of SIRT1/PGC-1α and AMPK signalling 52 , 53 , 153 and enhanced activation of the Akt/mTORC1 pathway in cardiomyocytes.…”

“… 150–152 This deficiency in autophagic capacity in heart failure is related to the simultaneous impairment of SIRT1/PGC-1α and AMPK signalling 52 , 53 , 153 and enhanced activation of the Akt/mTORC1 pathway in cardiomyocytes. 147 , 151 , 154 These derangements in longevity gene signalling is seen both experimentally and clinically.…”

Pyridostigmine Protects Against Diabetic Cardiomyopathy by Regulating Gut Microbiota and Branched-Chain Amino Acid Catabolism to Attenuate Mitochondria Dysfunction

“…The study showed that cardiac BCAA catabolism and insulin signaling was impaired in human heart failure, while enhancing BCAA oxidation could improve cardiac function in the failing mouse heart [53]. A previous study has suggested that miR-22 overexpression is coupled with PP2Cm downregulation, BCAA accumulation, and mTOR hyperactivation and is possibly linked to alterations in glucose utilization and suppression of autophagy in dilated cardiomyopathy [54]. Suppression of wholebody BCAA catabolism via deletion of PP2Cm elevates circulating and cardiac BCAA levels and worsens the cardiac response to ischaemia/reperfusion injury [55].…”