Abstract
Objectives The correlation between hyperhomocysteinemia and severity of coronary artery disease has been reported. In this study, we investigated the effect of hyperhomocysteinemia on myocardial ischemia/reperfusion (I/R) injury with elucidating the role of ER stress and autophagy to further the mechanistic understanding of the impact posed by hyperhomocysteinemia on cardiac function. Methods Hearts from male Wistar rats fed with regular or high-methionine diet (2%, wt/wt) for 8 weeks were mounted on a Langendorff apparatus and subjected to 30-min global ischemia followed by 60-min reperfusion. Endoplasmic reticulum (ER) stress inhibitor 4-phenybutyric acid (4-PBA) and tauroursodeoxycholic acid (TDUCA), or autophagy inhibitor 3-methyladenine (3-MA) and chloroquine (CQ) were perfused for 15 min prior to the onset of the ischemia. Left ventricular function was monitored throughout the experiment. The protein expression of ER stress molecules GRP78, PERK, and IRE1 as well as autophagy markers SQSTM1/p62 and LC3II/LC3I were determined by western blotting. Results I/R decreasedleft ventricular systolic pressure (LVSP) and increased end-diastolic pressure (LVEDP) in both control and hyperhomocysteinemic rats. Compared with the control animals, hyperhomocysteinemic rats showed lower LVSP, higher LVEDP, and lower left ventricular developed pressure (LVDP), as well as attenuated maximum velocity of contraction (+dp/dtmax) and relaxation (-dp/dtmax) of the left ventricle after I/R. Pretreatment with ER stress or autophagy inhibitors partially restored these hemodynamic parameters whereas the restoration was less significant in hyperhomocysteinemic rats as compared to the controls. Protein analysis showed a higher level of upregulation in GRP78 expression and PERK phosphorylation in hearts from hyperhomocysteinemic rats than control animals after I/R. The protein level of SQSTM1/p62 was significantly higher and the expression ratio of LC3B-II/LC3B-I was significantly lower in the heart of hyperhomocysteinemic rats as compared to the control hearts after subjected to I/R. Conclusions Hyperhomocysteinemia exacerbates myocardial I/R injury through worsening ER stress and regulating autophagy.
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