Restoring diabetes-induced autophagic flux arrest in ischemic/reperfused heart by ADIPOR (adiponectin receptor) activation involves both AMPK-dependent and AMPK-independent signaling

Abstract

Macroautophagy/autophagy is increasingly recognized as an important regulator of myocardial ischemia-reperfusion (MI-R) injury. However, whether and how diabetes may alter autophagy in response to MI-R remains unknown. Deficiency of ADIPOQ, a cardioprotective molecule, markedly increases MI-R injury. However, the role of diabetic hypoadiponectinemia in cardiac autophagy alteration after MI-R is unclear. Utilizing normal control (NC), high-fat-diet-induced diabetes, and Adipoq knockout (adipoq) mice, we demonstrated that autophagosome formation was modestly inhibited and autophagosome clearance was markedly impaired in the diabetic heart subjected to MI-R. adipoq largely reproduced the phenotypic alterations observed in the ischemic-reperfused diabetic heart. Treatment of diabetic and adipoq mice with AdipoRon, a novel ADIPOR (adiponectin receptor) agonist, stimulated autophagosome formation, markedly increased autophagosome clearance, reduced infarct size, and improved cardiac function (P < 0.01 vs vehicle). Mechanistically, AdipoRon caused significant phosphorylation of AMPK-BECN1 (Ser93/Thr119)-class III PtdIns3K (Ser164) and enhanced lysosome protein LAMP2 expression both in vivo and in isolated adult cardiomyocytes. Pharmacological AMPK inhibition or genetic Prkaa2 mutation abolished AdipoRon-induced BECN1 (Ser93/Thr119)-PtdIns3K (Ser164) phosphorylation and AdipoRon-stimulated autophagosome formation. However, AdipoRon-induced LAMP2 expression, AdipoRon-stimulated autophagosome clearance, and AdipoRon-suppressed superoxide generation were not affected by AMPK inhibition. Treatment with MnTMPyP (a superoxide scavenger) increased LAMP2 expression and stimulated autophagosome clearance in simulated ischemic-reperfused cardiomyocytes. However, no additive effect between AdipoRon and MnTMPyP was observed. Collectively, these results demonstrate that hypoadiponectinemia impairs autophagic flux, contributing to enhanced MI-R injury in the diabetic state. ADIPOR activation restores AMPK-mediated autophagosome formation and antioxidant-mediated autophagosome clearance, representing a novel intervention effective against MI-R injury in diabetic conditions.

Activation of autophagy inhibits nucleotide‐binding oligomerization domain‐like receptor protein 3 inflammasome activation and attenuates myocardial ischemia‐reperfusion injury in diabetic rats

“…Autophagy is inhibited in type 2 diabetes mellitus, whereas it is activated in type 1 diabetes mellitus 32 . The reasons for these inconsistencies are as follows: (i) different methods of autophagy detection lead to different interpretations of the results 33 ; and (ii) the impairment of autophagy varies at different stages of diabetes. In the preliminary experiment, we also found that autophagy was inhibited with 24 h high glucose treatment, but overactivated if treated with high glucose for 72 h. This might be the reason why autophagy has different roles in diabetes.…”

Examining the Potential of Developing and Implementing Use of Adiponectin-Targeted Therapeutics for Metabolic and Cardiovascular Diseases

“…AdipoRON effectively improved insulin sensitivity and restored glucose homeostasis via the activation of AdipoR1-AMPK-PGC1α and AdipoR2-PPARα signaling pathways (162). AdipoRON treatment also mimicked adiponectin's established anti-diabetic effects (163) and ability to enhance cellular capacity for mitigating oxidative-stress (162,164), enhancing lipid/glucose oxidation in mitochondria (162,164), anti-inflammatory responses (162,(164)(165)(166)(167), lifeprolonging effect (162,163), anti-cancer effects (168,169), procell survival and anti-apoptotic effect (170,171), neuronal- (172,173), reno- (174,175), and cardio-/vascular-protective effects (165,(176)(177)(178)(179). However, exciting AdipoRON research in animal models has not been translated to establishment of a drug for human use and the search continues for additional small molecule AdipoR agonists which have little or no toxicity.…”

The role of adiponectin in ischemia-reperfusion syndrome: a literature review

“…AdipoRon, via AMPK, stimulated the formation of these autophagosomes, increasing clearance, reducing infarction area, and improving cardiac function. (23,24) On the other hand, Zhang et al, stated that APN antioxidative and anti-inflammatory role does not occur via AMPK, but via protein kinase A (PKA). The researchers suggested that, when they administered APN 10 minutes before promoting IRS in the heart muscle, there was a decrease in oxidative stress and a reduction of the infarcted area in the study group.…”

“…AdipoRon, via AMPK, stimulated the formation of these autophagosomes, increasing clearance, reducing infarction area, and improving cardiac function. ( 23 , 24 )…”

“…O AdipoRon, via AMP-K, estimulou a formação destes autofagossomos, aumentando seu clearance , reduzindo a área de infarto, e melhorando a função cardíaca. ( 23 , 24 )…”