Low-Dose Propofol and Salvianolic Acid a Combination Attenuates Myocardial Ischemia/reperfusion-injured Mitochondrial Metabolism via AMPK/HDAC6 Pathway in Diabetes

Abstract ID 128798 Poster Board 266 Hearts with diabetic cardiomyopathy (DCM) are more vulnerable to myocardial ischemic-reperfusion injury (MIRI) and less or not sensitive to cardioprotective strategies, and the underlying mechanism remains largely unknown and effective treatment is lacking. As a widely used intravenous anesthetics and a reactive oxygen species scavenger, propofol (PPF) can attenuate diabetic MIRI at a high dose. We earlier found that low-dose PPF together with Salvianolic acid A (SAA), a potent antioxidant that confers cardioprotection, exerted synergistic effects against MIRI under diabetic conditions via regulating the CD36/AMPK pathway that influences energy metabolism. Diabetes and MIRI can both increase histone deacetylase 6 (HDAC6) activity that affects mitochondrial complex I (mCI), leading to exacerbated oxidative stress injuries. In spite of the common ground on mitochondrial metabolism, the regulation between AMPK and HDAC6 remains unknown. The present study aimed to determine whether PPF and SAA attenuate MIRI in diabetic mice via AMPK/HDAC6. We found that 30 minutes (min) of coronary followed by 2 hours of reperfusion resulted in more profound MIRI in high fat diet (HFD) and streptozotocin (STZ) induced type 2 diabetic mice compared with non-diabetic mice, manifested as larger infarct size and reduction of left ventricular ejective fraction (EF), along with decreased AMPK activity and mitochondrial complex I expression but increased HDAC6 levels (all p<0.05). The abovementioned negative consequences of MIRI in diabetes were reversed by the application of low-dose PPF (46mg/kg) combined with SAA (10mg/kg) during MIRI, and the effects were superior to that achieved with high dose PPF (92mg/kg). Inhibition of AMPK using Compound C significantly exacerbated MIRI, and cancelled the cardioprotection produced by PPF and SAA. The findings are suggestive that PPF combined with SAA could confer superior cardioprotective effects against MIRI to the usage of high dose PPF alone by upregulating p-AMPK to inhibit HDAC6 in diabetic hearts.