LuQi Formula relieves ventricular remodeling through improvement of HIF-1α-mediated intestinal barrier integrity

Abstract

Background Ventricular remodeling is the adaptive process in which the heart undergoes changes due to stress, leading to heart failure (HF). The progressive decline in cardiac function is considered to contribute to intestinal barrier impairment. LuQi Formula (LQF) is a traditional Chinese medicine preparation widely used in the treatment of ventricular remodeling and HF. However, the role of LQF in the impairment of intestinal barrier function induced by ventricular remodeling remains unclear. Materials and methods Ventricular remodeling was induced in rats by permanently ligating the left anterior descending branch coronary artery, and cardiac function indexes were assessed using echocardiography. Heart and colon tissue morphology were observed by hematoxylin–eosin, Masson’s trichrome and Alcian Blue Periodic acid Schiff staining. Myocardial cell apoptosis was detected using TUNEL and immunohistochemistry. Circulatory levels of brain natriuretic peptide (BNP), intestinal permeability markers endotoxin, D-lactate and zonulin, as well as inflammatory cytokines tumor necrosis factor alpha and interleukin-1 beta were measured by Enzyme-linked immunosorbent assay. Expression levels of tight junction (TJ) proteins and hypoxia-inducible factor-1 alpha (HIF-1α) in colon tissue were detected by immunofluorescence, immunohistochemistry and western blotting. Cardiac function indexes and intestinal permeability markers of patients with HF were analyzed before and after 2–4 months of LQF treatment. Results LQF protected cardiac function and alleviated myocardial fibrosis and apoptosis in rats with ventricular remodeling. LQF protected the intestinal barrier integrity in ventricular remodeling rats, including maintaining colonic tissue morphology, preserving the number of goblet cells and normal expression of TJ proteins. Furthermore, LQF upregulated the expression of HIF-1α protein in colon tissue. Intervention with a HIF-1α inhibitor weakened the protective effect of LQF on intestinal barrier integrity. Moreover, a reduction of HIF-1α aggravated ventricular remodeling, which could be alleviated by LQF. Correspondingly, the circulating levels of intestinal permeability markers and BNP in HF patients were significantly decreased, and cardiac function markedly improved following LQF treatment. Conclusions We demonstrated that LQF effectively protected cardiac function by preserving intestinal barrier integrity caused by ventricular remodeling, at least partially through upregulating HIF-1α expression.