Loganin ameliorates left ventricular fibrosis and dysfunction induced by pressure overload via the Sirt1/AKT/TGF-β1...

Loganin (LG), a natural compound derived from Cornus officinalis Sieb. et Zucc., possesses diverse pharmacological properties, such as anti-inflammatory, anti-hypertrophic, and antioxidant effects. However, the role of LG in the pathogenesis of Heart Failure (HF) remains unclear. The current work aimed to explore the underlying mechanism of LG in pressure overload-induced HF, both in vivo and in vitro, using transverse aortic constriction (TAC) surgery or isoproterenol (ISO) administration. Following eight weeks of TAC surgery, histological assessments, including hematoxylin and eosin staining, wheat germ agglutinin staining, TUNEL assay, and Masson's trichrome staining, were conducted to evaluate the extent of cardiomyocyte remodeling. Additionally, RT-PCR and WB analyses were performed to detect the levels of various targets. Furthermore, H9C2 cardiomyocytes were treated with ISO to induce hypertrophy, and the effects of LG on cell viability, α-smooth muscle actin (α-SMA) expression, and molecular targets were investigated. Our findings revealed that LG treatment at 40 mg/kg/day significantly attenuated cardiac dysfunction, decreased left ventricular collagen deposition in both interstitial and perivascular spaces. Mechanistically, LG mitigated ISO-induced toxicity in H9C2 cardiomyocytes, decreasing cellular hypertrophy and α-SMA expression. Moreover, we observed a downregulation of Sirtuin 1 (Sirt1) at the molecular level, accompanied by reduced phosphorylation of Akt and transforming growth factor-β1 (TGF-β1). Notably, the administration of the Sirt1 inhibitor, EX527, effectively abolished the protective effects of LG. Therefore, the cardio-protective effects of LG were mediated through the activation of the Sirt1/Akt/TGF-β1 signaling pathway, leading to reduced fibrosis and improved cardiac function.