Protective Effect Of Protocatechuic Acid On Heart Of Rats With Experimental MI And Its Mechanism

BackgroundThe major causes of death in the world include five chronic diseases,cancer,cardiovascular disease(CVD),chronic obstructive pulmonary disease(COPD),type II diabetes mellitus(T2D)and Alzheimer’s disease(AD;World Health Organization data,2018).Chronic diseases affect about 133 million Americans and 6 million Canadians,accounting for more than 60% of all deaths worldwide(World Health Organization data,2018).Oxidative stress is considered as a contributing factor to the development of these diseases.Therefore,understanding the potential mechanisms related to oxidative stress is crucial for prevention and/or development of treatment strategies.ObjectiveThe aim of the experiment was to investigate the potential cardioprotective effect of protocatechuic acid(PCA)in the experimental MI rat model mediated by isoproterenol(ISO)injection.To study the effects of PCA on redox homeostasis,inflammation,apoptosis,fibrosis and Nrf2/HO-1 signal pathway in the heart of rats with MI.MethodsRats(Wistar rats,12 weeks,weighing 180 – 200 g,n = 35)were placed in polypropylene cages(25℃ under normal light/dark cycle),adapt to controlled laboratory conditions within 10 days,feed standard rodent feed and drink water freely.After the adaptation period,the rats were randomly divided into the following five groups(n =7): control,isoproterenol(85 mg/kg),protocatechuic acid(200 mg/kg),protocatechuic acid(100 mg/kg)+ isoproterenol and protocatechuic acid(200 mg/kg)+ isoproterenol groups.The process last for 14 days.The expected parameters will include:Heart function markers: Serum creatine kinase,lactate dehydrogenase and alkaline phosphatase.Oxidative stress and antioxidants markers:Lipid peroxide malondialdehyde,nitric oxide,reduced glutathione,glutathione peroxidase,glutathione reductase,superoxide dismutase,catalase,nuclear factor erythrocyte 2 related factor 2(Nrf2)and heme oxygenase-1(HO-1).Inflammatory markers: TNF-a,IL-1β and NF-κB Apoptosis markers: Bcl2,Bax and caspase.Fibrosis markers:TGF-β1,metalloproteinase-9(MMP-9)and metalloproteinase-3(TIMP-3).The myocardial tissue was examined by histopathology.ResultsPCA supplementation markedly reduced ISO-induced disturbed cardiac function markers(creatine kinase,lactate dehydrogenase,and troponin T).Notably,PCA administration exerted remarkable increases in glutathione and its derived enzymes,superoxide dismutase,and catalase,as well as decreases in malondialdehyde and nitric oxide levels in the injured cardiac tissue.The findings validated the augmented cellular antioxidative capacity by PCA via increasing the gene expressions of nuclear factor erythroid 2-related factor 2 and heme oxygenase-1.The cardioprotective efficacy of PCA extended to suppress the cardiac inflammation as demonstrated by the decreased levels of tumor necrosis factor-alpha,interleukin-1 beta,and nuclear factor kappa B in rats.Additionally,PCA prevented the cardiomyocytes loss and fibrosis by decreasing Bax,caspase-3,transforming growth factor-β1 and matrix MMP-9,and enhancing Bcl-2 and tissue inhibitors of TIMP-3.Conclusion1.PCA plays a protective role in myocardial infarction induced by ISO by restoring the level of cardiac function markers.2.PCA restored the imbalance between oxidative stress indicators(malondialdehyde and nitric oxide),Nrf2 and its downstream antioxidant molecules and antioxidant system in heart tissue.3.PCA inhibited inflammatory mediators(tumor necrosis factor-α,IL-1β,and nuclear factor-κb),apoptosis,and fibrosis in the Rat Heart.