Hydrochlorothiazide Improves Cardiac Remodeling in Heart Failure Rats by Reducing Oxidative Stress

Background and Aims: The impact of thiazide diuretics on cardiac remodeling and prognosis in heart failure remains uncertain. This study aims to investigate whether hydrochlorothiazide can improve cardiac function and remodeling by inhibiting oxidative stress.

Methods: The rat model of heart failure was established by ligating the left anterior descending branch of the coronary artery, and hydrochlorothiazide (12.5 mg/kg, ig, Qd) was administered by gavage for 6 weeks. The cardiac function was evaluated using echocardiography and hemodynamics. Various methodologies were used to evaluate the effects of hydrochlorothiazide on myocardial fibrosis, inflammation, oxidative stress, and apoptosis. The effects of hydrochlorothiazide were validated in vitro using H9c2 cell cultures. The binding mechanism of hydrochlorothiazide to carbonic anhydrase 2 (CAII) was investigated using molecular docking and dynamics simulations.

Results: The decreases in ejection fraction, fractional shortening, and left ventricular end-systolic pressure and the increases in left ventricular end-diastolic diameter, left ventricular end-diastolic pressure, and B-type natriuretic peptide in heart failure rats were improved by hydrochlorothiazide. Hydrochlorothiazide can reduce the expression of myocardial collagen I. In terms of oxidative stress, hydrochlorothiazide can decrease MDA, p47phox, and p67phox while increasing SOD2, total oxidation capacity, and mitochondrial respiratory chain complexes I and IV. Additionally, hydrochlorothiazide can inhibit the p38MAPK/JNK signaling pathway, leading to reduced expression of inflammatory markers (NF-ĸB p65) and apoptotic markers (Bax, caspase3, and cytochrome C). The possible mechanism involves hydrochlorothiazide inhibiting the expression of sodium hydrogen exchanger 1 (NHE1), which is an upstream molecule involved in oxidative stress. H9c2 cell culture further confirmed the effects of hydrochlorothiazide on oxidative stress, inflammation, and apoptosis. Molecular docking and dynamics simulation results demonstrated that hydrochlorothiazide directly binds to CAII forming an unstable conformation. Gene knockout studies showed that CAII knockout reduces the expression of NHE1, NCX1, p67phox, Bax, and NF-ĸB p65.

Conclusions: Hydrochlorothiazide can enhance cardiac function and mitigate cardiac fibrosis remodeling in rats with heart failure by reducing the oxidative stress and inhibiting the p38MAPK/JNK signaling pathway, wherein CAII and NHE1 play a crucial role.