Protocatechuic acid attenuates isoproterenol-induced heart failure by modulating cardiac oxidative stress, LDL-R/SREBP-2/PPAR-α, and Bax/Bcl-2 /Bcl-xL/Cyt.c/ Caspase - 9 and Caspase - 3 pathways.

Worldwide, heart failure (HF) is among the top causes of morbidity and mortality. Curative interventions using natural products for cardiovascular diseases have gained substantial attention worldwide. At present, there is little research on the protective mechanisms of protocatechuic acid in HF. Hence, we evaluated the protective mechanisms of protocatechuic acid on cardiac oxidative stress, low-density lipoprotein- receptor (LDL-R)/ sterol regulatory element-binding protein-2 (SREBP-2)/peroxisome proliferator-activated receptor-α(PPAR-α) and B-cell lymphoma-2 associated-x (Bax)/ B-cell lymphoma gene-2(Bcl-2)/B-cell lymphoma-extra large(Bcl-xL)/Cytochrome c (Cyt.c)/Caspase-3/Caspase -9 pathways in isoproterenol-induced HF rats. Rats were induced HF by isoproterenol (5 mg/kg body weight) daily for 7 days. Then, rats were treated with protocatechuic acid (16 mg/kg body weight) for four weeks. The serum HF diagnostic marker and heart lipid hydroperoxides were increased and systolic and diastolic pressure and heart antioxidants were reduced in the isoproterenol-induced HF rats. Moreover, serum and heart total cholesterol, triglycerides, and serum low-density lipoprotein-cholesterol and liver 3-hydroxy-3 -methylglutaryl coenzyme A reductase were elevated and serum high density lipoprotein- cholesterol was reduced in the HF rats. Furthermore, lipid peroxidation products in the heart lysosomal fraction and lysosomal enzymes in the serum and heart were increased.A reverse transcription-polymerase chain reaction study revealed altered expression of hepatic LDL-R, SREBP-2, and PPAR- α and myocardial expression of Bax, Bcl-2, Bcl-xL, Cyt.c, Caspases-3, and -9 genes. Nevertheless, HF rats treated with protocatechuic acid considerably attenuated all the hemodynamic, biochemical, molecular, transmission electron microscopic, and histological parameters investigated and protected HF rats, by its potent antioxidant, anti-hyperlipidemic and anti-apoptotic mechanisms.