HINT2 deficiency deteriorates oxidative stress in a mouse model of myocardial infarction

Abstract

Abstract Aims Myocardial infarction (MI) is one of the serious diseases with great mortality over the world. Myocardial mitochondrial oxidative stress has been implicated as a key player in MI. The histidine triad nucleotide‐binding protein 2 (HINT2) is a nucleotide hydrolase and transferase located in mitochondria. HINT2 has multiple functions such as regulating mitochondrial lipid metabolism and respiration and glucose homeostasis. Although HINT2 has been shown to protect against MI, the underlying mechanisms were not fully elucidated. In this study, the effects of HINT2 on oxidative stress during MI were explored. Methods and results MI mouse models in both wild‐type and HINT2‐deficient mice were established. The expression of HINT2 in HINT2‐deficient mice was determined by quantitative real‐time PCR and western blot. The levels of oxidative stress were measured, including the levels of malondialdehyde (MDA), nitric oxide (NO), superoxide dismutase (SOD), and glutathione (GSH). The myocardial functions, as indicated by left ventricular end‐diastolic diameter (LVEDD), left ventricular end‐systolic diameter (LVESD), left ventricular ejection fraction (LVEF), and left ventricular fractional shortening (LVFS), were monitored. Both mRNA and protein expressions of HINT2 in the myocardial tissues were significantly down‐regulated in MI mice starting at 6 h post‐MI. MI induced oxidative stress 6 h post‐MI in myocardial tissues of wild‐type mice, as suggested by the enhanced MDA and NO levels and decreased SOD and GSH levels. The expression of HINT2 was negatively correlated to the MDA and NO levels and positively correlated to the SOD and GSH levels. HINT2‐deficient MI mice had significantly elevated levels of MDA and NO and significantly decreased levels of SOD and GSH when compared with wild‐type MI mice. HINT2‐deficient MI mice had higher LVEDD and LVESD and lower LVEF and LVFS compared with wild‐type MI mice, indicating that HINT2 deficiency exacerbated myocardial dysfunction. Conclusions HINT2 deficiency causes deteriorative oxidative stress in MI mice, leading to exacerbated myocardial dysfunction.

Keywords

• Myocardial infarction
• HINT2
• Deficiency
• Oxidative stress