Decreased autophagy: a major factor for cardiomyocyte death induced by β1-adrenoceptor autoantibodies

Abstract

Cardiomyocyte death is one major factor in the development of heart dysfunction, thus, understanding its mechanism may help with the prevention and treatment of this disease. Previously, we reported that anti-β1-adrenergic receptor autoantibodies (β1-AABs) decreased myocardial autophagy, but the role of these in cardiac function and cardiomyocyte death is unclear. We report that rapamycin, an mTOR inhibitor, restored cardiac function in a passively β1-AAB-immunized rat model with decreased cardiac function and myocardial autophagic flux. Next, after upregulating or inhibiting autophagy with Beclin-1 overexpression/rapamycin or RNA interference (RNAi)-mediated expression of Beclin-1/3-methyladenine, β1-AAB-induced autophagy was an initial protective stress response before apoptosis. Then, decreased autophagy contributed to cardiomyocyte death followed by decreases in cardiac function. In conclusion, proper regulation of autophagy may be important for treating patients with β1-AAB-positive heart dysfunction.

Decreased autophagy induced by β1-adrenoceptor autoantibodies contributes to cardiomyocyte apoptosis

“…β 1 -AABs that interacted with β 1 -AR had an agonist-like effect 24 , and β 1 -AR could significantly affect autophagy 25 . Our preliminary studies found that the levels of autophagy in the myocardium were decreased markedly both in actively and passively immunized rats, and the autophagy decline was involved in cardiac dysfunction induced by β 1 -AABs 7 , 26 . In the present study, we found that the level of autophagy increased significantly at 1 day and 1 week after active immunization with β 1 -AR-ECII.…”

“…Impaired organelles or incorrectly folded proteins are degraded by autophagy in order to provide a critical means for cell self-renewal, energy repletion, and substrate recycling 6 . In preliminary studies, our group has shown that decreased autophagy induced by β 1 -AABs contributed to cardiomyocyte death and cardiac dysfunction 7 . In certain circumstances, autophagy, as a stress response, can protect cells from death by inhibiting apoptosis 8 , while the inhibition of autophagy by 3-methyladenine (3-MA) or the silencing of Atg5 or Atg7 could activate caspase-3 and subsequently apoptosis 9 .…”

Myocardial stress and autophagy: mechanisms and potential therapies

“…Cardiomyocyte death induced by β-adrenergic autoantibodies is linked with decreased autophagy and is rescued by rapamycin-induced autophagy activation. 76 Recently, the attachment of small ubiquitin-like modifier proteins (SUMOylation) onto autophagy proteins has been demonstrated, coincident with upregulation of autophagy, improved protein quality control and decreased morbidity in cardiac proteotoxic disease. 77 …”

Adrenoceptor regulation of the mechanistic target of rapamycin in muscle and adipose tissue

“…In the early stages of heart failure, cardiac output is increased via overstimulation of β 1 ‐adrenoceptors as a compensatory mechanism for the insufficient blood and oxygen supply (Brodde, ), but this leads to longer term structural damage, including ventricular remodelling, cardiomyocyte apoptosis and fibrosis, and cardiac hypertrophy (Engelhardt, Hein, Wiesmann, & Lohse, ; O'Connor et al, ). In addition, recent evidence has shown that β 1 ‐adrenoceptors decrease myocardial autophagy that maintains cellular homeostasis (Wang et al, ; Wang et al, ). Inhibition of autophagy causes the accumulation of denatured proteins and damaged organelles, contributing to cardiac dysfunction (Magnusson, Wallukat, Waagstein, Hjalmarson, & Hoebeke, ), and up‐regulation of autophagy by the mTORC1 inhibitor rapamycin can improve impaired cardiac function (Wang et al, ).…”

“…In addition, recent evidence has shown that β 1 ‐adrenoceptors decrease myocardial autophagy that maintains cellular homeostasis (Wang et al, ; Wang et al, ). Inhibition of autophagy causes the accumulation of denatured proteins and damaged organelles, contributing to cardiac dysfunction (Magnusson, Wallukat, Waagstein, Hjalmarson, & Hoebeke, ), and up‐regulation of autophagy by the mTORC1 inhibitor rapamycin can improve impaired cardiac function (Wang et al, ). The β 1 ‐adrenoceptor‐mediated inhibition of autophagy occurs via PKA phosphorylation of Ser 12 in the autophagy‐related protein LC3 (Kroemer, Zamzami, & Susin, ).…”