Combination of D942 with curcumin protects cardiomyocytes from ischemic damage through promoting autophagy

Myocardial ischemia is one of the main causes of sudden cardiac death. Autophagy has been demonstrated to protect cardiomyocytes from ischemia/reperfusion (I/R)-induced damage. A small molecule compound 5-(3-(4-(2-(4-fluorophenyl)ethoxy)phenyl)propyl)furan-2-carboxylic acid (D942) has been previously shown to specifically activate adenosine monophosphate-activated protein kinase (AMPK) in cancer cells. Another reagent, curcumin, has been shown to inhibit mammalian target of rapamycin (mTOR) signal pathway in tumor cells. Since AMPK signaling induces autophagy, while mTOR signaling inhibits autophagy, here we tested the potential protective efficacy of D942 with curcumin for cardiomyocytes under oxygen-glucose deprivation and reoxygenation (OGD/R). Mouse neonatal cardiomyocytes were treated with D942 and curcumin after being subjected to OGD/R. Cell survival and autophagy-related signal pathways were measured after treatment. Our data indicated both D942 and curcumin enhanced cell survival after OGD/R. The D942 and curcumin induced autophagy in cardiomyocytes through activating AMPK pathway or inhibiting mTOR signaling. Induction of autophagy by D942 and curcumin was the cause of cardioprotection, since inhibition of autophagy abolished the protective efficacy. Furthermore, combination treatment with D942 and curcumin profoundly upregulated autophagy after OGD/R and significantly promoted cell survival. Treatment with D942 and curcumin significantly upregulated autophagy in a murine myocardial I/R model. Taken together, our research suggests that D942 and curcumin could be promising therapeutic agents for myocardial I/R.