Experimental diabetes exacerbates autophagic flux impairment during myocardial I/R injury through calpain‐mediated cleavage of Atg5/LAMP2

Abstract

To explore the role of autophagic flux in the increased susceptibility of the experimental diabetic heart to ischaemia‐reperfusion (I/R) injury, we established STZ‐induced diabetic mice and performed I/R. In vitro, neonatal mouse cardiomyocytes were subjected to high glucose and hypoxia/reoxygenation challenge to mimic diabetic I/R injury. We found that experimental diabetes aggravated I/R‐induced injury than compared with nondiabetic mice. Autophagic flux was impaired in I/R hearts, and the impairment was exacerbated in diabetic mice subjected to I/R with defective autophagosome formation and clearance. Calpains, calcium‐dependent thiol proteases, were upregulated and highly activated after I/R of diabetes, while calpain inhibition attenuated cardiac function and cell death and partially restored autophagic flux. The expression levels of Atg5 and LAMP2, two crucial autophagy‐related proteins, were significantly degraded in diabetic I/R hearts, alterations that were associated with calpain activation and could be reversed by calpain inhibition. Co‐overexpression of Atg5 and LAMP2 reduced myocardial injury and normalized autophagic flux. In conclusion, experimental diabetes exacerbates autophagic flux impairment of cardiomyocytes under I/R stress, resulting in worse I/R‐induced injury. Calpain activation and cleavage of Atg5 and LAMP2 at least partially account for the deterioration of autophagic flux impairment.

Calpain and Cardiometabolic Diseases

“…Autophagy-related proteins, autophagy-related 5 (Atg5) and lysosome-associated membrane protein 2 (LAMP2), underwent degradation in diabetic ischemia-reperfusion-afflicted myocardium due to calpain activation, whereas their levels were restored upon calpain inhibition. Co-overexpression of Atg5 and LAMP2 ameliorated myocardial injury and normalized autophagic flux [98]. Therefore, hyperglycemia abrogates ischemia-reperfusion-induced autophagic flux, thereby inducing cardiac dysfunction, which is attributed to calpain activation and cleavage of Atg5/LAMP2.…”

“…These discoveries underscore the pivotal role of calpain in diabetic cardiomyopathy through the suppression of β-catenin. Another series of investigations identified the role of conventional calpains in heightened susceptibility to ischemia-reperfusion injury in diabetic myocardium in mice [98]. Autophagic flux exhibited compromise within ischemia-reperfusion-subjected hearts, particularly in diabetic subjects, manifesting as impaired autophagosome formation and clearance mechanisms.…”

“…Autophagic flux exhibited compromise within ischemia-reperfusion-subjected hearts, particularly in diabetic subjects, manifesting as impaired autophagosome formation and clearance mechanisms. Conventional calpains were extensively activated in diabetic ischemia-reperfusion models, and the inhibition of calpain activity demonstrated improvements in cardiac function, a reduction in cell mortality, and a partial restoration of autophagic flux [98]. Autophagy-related proteins, autophagy-related 5 (Atg5) and lysosome-associated membrane protein 2 (LAMP2), underwent degradation in diabetic ischemia-reperfusion-afflicted myocardium due to calpain activation, whereas their levels were restored upon calpain inhibition.…”

Autophagy in Heart Failure: Insights into Mechanisms and Therapeutic Implications

“…Of note, diabetic mice and rats are more susceptible to myocardial infarction and, in the ischemia-reperfusion model, develop greater infarct size [ 96 , 134 ]. The activation of autophagy either by the genetic overexpression of Atg5 and Lamp2 or pharmacologically with rapamycin or metformin reduced infarct size in diabetic animals [ 96 , 134 ].…”

“…Of note, diabetic mice and rats are more susceptible to myocardial infarction and, in the ischemia-reperfusion model, develop greater infarct size [ 96 , 134 ]. The activation of autophagy either by the genetic overexpression of Atg5 and Lamp2 or pharmacologically with rapamycin or metformin reduced infarct size in diabetic animals [ 96 , 134 ]. Interestingly, the injection of rapamycin shortly before the reperfusion phase preserved postinfarction cardiac function and reduced fibrosis in diabetic rabbits subjected to ischemia-reperfusion [ 135 ].…”