LOX-1 promotes cardiac hypertrophy via p38MAPK signaling in alcoholic cardiomyopathy

Cardiac hypertrophy is a hallmark of alcoholic cardiomyopathy (ACM). The role of Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1)/p38MAPK in mediating hypertrophy in ACM remains unclear. Primary neonatal rat ventricular cardiomyocytes (pNRVMs) were treated with ethanol and transfected with shRNA or overexpression constructs targeting LOX-1 or p38MAPK to investigate their roles in ethanol-induced cardiomyocyte hypertrophy, autophagy, and apoptosis. Sprague-Dawley rats were administered with ethanol to establish ACM models. H&E staining was used to assess cellular morphology, and transmission electron microscopy was used to detect autophagosomes. Apoptosis was detected by flow cytometry and TUNEL staining. RT‑qPCR and Western blot were used to determine the expression levels of LOX‑1, p38MAPK, and markers related to hypertrophy, autophagy, and apoptosis. Cardiac function parameters were measured by echocardiography. In pNRVMs, alcohol promoted p‑p38MAPK/p38MAPK expression via upregulation of LOX‑1, which inhibited autophagy (elevated Beclin‑1, ATG5, LC3‑II/LC3‑I, LAMP1 and p62) and subsequently promoted cardiomyocyte hypertrophy (upregulated ANP, BNP, MEF2C, and β‑MHC, with downregulated α‑MHC) and apoptosis (increased Bax and cleaved caspase‑3). LOX‑1 overexpression exacerbated these alterations, whereas LOX‑1 knockdown partially reversed them. P38MAPK overexpression partially counteracted the effects conferred by LOX‑1 knockdown. LOX‑1 knockdown similarly enhanced autophay and suppressed hypertrophic and apoptotic markers, improved cardiac function (elevated EF and FS), reduced hypertrophy indices (HW/TL and LVM/TL), and lowered serum injury markers (LDH, cTnI, and CK‑MB) in ACM rats. Histological and TUNEL staining further supported the alleviation of myocardial hypertrophy and apoptosis. LOX-1 knockdown promotes p38MAPK-mediated autophagy, effectively suppressing myocardial hypertrophy and consequent apoptosis, and ultimately ameliorating ACM.