Asiatic Acid Attenuates Myocardial Ischemia/Reperfusion Injury via Akt/GSK-3β/HIF-1α Signaling in Rat H9c2 Cardiomyocytes

Abstract

Myocardial ischemic/reperfusion injury results from severe impairment of coronary blood supply and leads to irreversible cell death, with limited therapeutic possibilities. Asiatic acid is a pentacyclic triterpenoid derived from the tropical medicinal plant Centella asiatica and serves a variety of bioactivities. In this study, we determined the effect of asiatic acid on myocardial ischemia/reperfusion injury and investigated the underlying mechanisms, using an in vitro rat H9c2 cardiomyocytes model of oxygen-glucose deprivation/reoxygenation (OGD/R) injury. Results showed that pre-treatment with asiatic acid significantly augmented cell viability and prevented lactate dehydrogenase (LDH) release in a concentration-dependent manner after OGD/R exposure. Asiatic acid at 10 µM effectively inhibited apoptotic cell death, suppressed the activities of caspase-3 and caspase-9, and reversed Bax/Bcl-2 ratio in hypoxic H9c2 cells. In addition, asiatic acid improved mitochondrial function, as evidenced by reduced reactive oxygen species (ROS) accumulation, enhanced mitochondrial membrane potential and decreased intracellular calcium concentration. Using Western blot assay, we found that asiatic acid promoted the phosphorylation of Akt and subsequent inactivation of glycogen synthase kinase-3β (GSK-3β), and induced the expression of hypoxia-inducible factor 1α (HIF-1α) after OGD/R. The cardioprotective effects of asiatic acid were attenuated by the Akt or HIF-1α inhibitor. Taken together, these data suggested that asiatic acid exerted protective effects against OGD/R-induced apoptosis in cardiomyocytes, at least partly via the Akt/GSK-3β/HIF-1α pathway.

Asiatic acid enhances survival of human AC16 cardiomyocytes under hypoxia by upregulating miR‐1290

“…Asiatic acid (AA) is a natural pentacyclic triterpene derived from Centella asiatica (Apiaceae family). A recent study by Huang et al suggested AA could protect rat H9c2 cardiomyocytes against oxygen‐glucose deprivation/reoxygenation induced apoptosis partly via the Akt/GSK‐3β/HIF‐1α pathway. Kim et al investigated the effect of AA treatment on the miRNA expression profiles of human non‐small cell lung cancer A549 cells and found miR‐1290 was significantly increased by 44.56 fold, suggesting AA may play its biologic role through regulating miR‐1290.…”

The Key Roles of GSK-3β in Regulating Mitochondrial Activity

“…Triptolide has been shown to potentially exhibit anti-inflammatory and autoimmune-suppressive activities, accompanied by severe toxicities, such as cardiac and liver damage [84]. It has been demonstrated that selective inhibition of GSK-3β by SB216763 may significantly ameliorate the adverse effects of triptolide in H9c2 cells through inhibition of CyP-D phosphorylation and modulation of Bcl-2 family proteins, leading to desensitization of mPTP and prevention of mitochondrial apoptosis [85].…”

“…Proanthocyanidins, an effective free radical scavenger, ameliorates anoxia-reoxygenation injury through activation of PI3K-Akt-GSK-3β signaling pathway and mK ATP channel pathway in myocardial cells [82]. Asiatic acid, a pentacyclic triterpenoid isolated from Centella asiatica , exhibits protective effects against myocardial I/R injury, as indicated by improved mitochondrial functions through Akt-GSK-3β-HIF-1α signaling in hypoxic H9c2 cells [83]. …”

Cardiovascular Protective Effects of Centella asiatica and Its Triterpenes: A Review

“…The protective effect of C. asiatica extracts and its triterpenes against cardiac hypertrophy and myocardial ischemia have been demonstrated in several in vitro studies (▶ Table 1) [31][32][33][34]. These studies suggested that asiatic acid, one of the triterpenes of C. asiatica, exerts protective effects in cardiomyocytes by activating or deactivating key signaling pathways involved in the pathogenesis of cardiac hypertrophy and myocardial ischemia.…”