Adiponectin up‐regulates the decrease of myocardial autophagic flux induced by β₁‐adrenergic receptor autoantibody partly dependent on AMPK

Abstract

Cardiomyocytes autophagy is essential for maintaining cardiac function. Our previous studies have found that β1‐adrenergic receptor autoantibody (β1‐AA) induced the decreased myocardial autophagic flux, which resulted in cardiomyocyte death and cardiac dysfunction. And other studies demonstrated that β1‐AA induced the decrease of AMPK phosphorylation, the key hub of autophagy pathway, while adiponectin up‐regulated autophagic flux mediated by AMPK. However, it is not clear whether adiponectin improves the inhibition of myocardial autophagic flux induced by β1‐AA by up‐regulating the level of AMPK phosphorylation. In this study, it has been confirmed that β1‐AA induced the decrease of AMPK phosphorylation level in both vivo and vitro. Moreover, pretreatment of cardiomyocytes with AMPK inhibitor Compound C could further reduce the autophagic flux induced by β1‐AA. Adiponectin deficiency could aggravate the decrease of myocardial AMPK phosphorylation level, autophagic flux and cardiac function induced by β1‐AA. Further, exogenous adiponectin could reverse the decline of AMPK phosphorylation level and autophagic flux induced by β1‐AA and even reduce cardiomyocyte death. While pretreated with the Compound C, the adiponectin treatment did not improve the decreased autophagosome formation, but still improved the decreased autophagosome clearance induced by β1‐AA in cardiomyocytes. This study is the first time to confirm that β1‐AA could inhibit myocardial autophagic flux by down‐regulating AMPK phosphorylation level. Adiponectin could improve the inhibition of myocardial autophagic flux induced by β1‐AA partly dependent on AMPK, so as to provide an experimental basis for the treatment of patients with β1‐AA‐positive cardiac dysfunction.

Ischemia‐induced cardiac dysfunction is exacerbated in adiponectin‐knockout mice due to impaired autophagy flux

“…The mechanisms behind these effects remain to be fully defined. We and others have now demonstrated that adiponectin stimulates autophagy flux in cardiomyocytes 21,32,33 . The link between autophagy and cell death in models of MI has been previously established 4,34 and the majority of studies indicate that induction of autophagy is a protective mechanism that reduces the extent of ischemia‐induced acute cell damage and also reduces the extent of postinfarction cardiac remodeling and dysfunction 6,35 .…”

“…Other studies have also indicated that adiponectin can directly stimulate myocardial autophagy and consequently confer cardioprotection. 21,32,33 Using echocardiography, including strain analysis, we observed that mice lacking adiponectin had an enhanced degree of cardiac dysfunction. Correlated with this was a significant increase in indices of cell death, such as more TUNEL positive cells and increased Bcl2:BAX ratio in Ad-KO versus WT mice after ischemia.…”

“…We and others have now demonstrated that adiponectin stimulates tophagy flux in cardiomyocytes. 21,32,33 The link between autophagy and cell death in models of MI has been previously established 4,34 and the majority of studies indicate that induction of autophagy is a protective mechanism that reduces the extent of ischemia-induced acute damage and also reduces the extent of postinfarction remodeling and dysfunction. 6,35 Nevertheless, it should also be noted that it has been demonstrated that cardiomyocytes can go through various forms of cell death during MI and that excess autophagy may in fact contribute to autophagic cell death.…”

“…Ad‐KO mice cannot accumulate adiponectin in damaged myocardium and have a disrupted autophagy flux when compared to WT after chronic myocardial ischemia. Other studies have also indicated that adiponectin can directly stimulate myocardial autophagy and consequently confer cardioprotection 21,32,33 …”

Role of adiponectin in osteoarthritis

“…AdipoRon treatment promotes autophagy and improves renal fibrosis in salt-hypertensive mice by activating the AMPK/ULK1 pathway ( Li et al, 2021 ). Notably, in cardiomyocytes pretreated with compound C, the adiponectin treatment did not improve the decreased autophagosome formation but improved the decreased autophagosome clearance induced by β1-adrenergic receptor autoantibody ( Sun et al, 2021 ). Exercise leads to AMPK activation in the muscle in normal mice but not in autophagy-defective mice ( Garber, 2012 ).…”