Low-intensity pulsed ultrasound of different intensities differently affects myocardial ischemia/reperfusion injury by modulating cardiac oxidative stress and inflammatory reaction.

INTRODUCTION

The prevalence of ischemic heart disease has reached pandemic levels worldwide. Early revascularization is currently the most effective therapy for ischemic heart diseases but paradoxically induces myocardial ischemia/reperfusion (MI/R) injury. Cardiac inflammatory reaction and oxidative stress are primarily involved in the pathology of MI/R injury. Low-intensity pulsed ultrasound (LIPUS) has been demonstrated to reduce cell injury by protecting against inflammatory reaction and oxidative stress in many diseases, including cardiovascular diseases, but rarely on MI/R injury.

METHODS

This study was designed to clarify whether LIPUS alleviates MI/R injury by alleviating inflammatory reaction and oxidative stress. Simultaneously, we have also tried to confirm which intensity of the LIPUS might be more suitable to ameliorate the MI/R injury, as well as to clarify the signaling mechanisms. MI/R and simulated ischemia/reperfusion (SI/R) were respectively induced in Sprague Dawley rats and human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs). LIPUS treatment, biochemical measurements, cell death assay, estimation of cardiac oxidative stress and inflammatory reaction, and protein detections by western blotting were performed according to the protocol.

RESULTS

In our study, both in vivo and in vitro, LIPUS of 0.1 W/cm (LIPUS) and 0.5 W/cm (LIPUS) make no significant difference in the cardiomyocytes under normoxic condition. Under the hypoxic condition, MI/R injury, inflammatory reaction, and oxidative stress were partially ameliorated by LIPUS but were significantly aggravated by LIPUS of 2.5 W/cm (LIPUS) both in vivo and in vitro. The activation of the apoptosis signal-regulating kinase 1 (ASK1)/c-Jun N-terminal kinase (JNK) pathway in cardiomyocytes with MI/R injury was partly rectified LIPUS both in vivo and in vitro.

CONCLUSION

Our study firstly demonstrated that LIPUS of different intensities differently affects MI/R injury by regulating cardiac inflammatory reaction and oxidative stress. Modulations on the ASK1/JNK pathway are the signaling mechanism by which LIPUS exerts cardioprotective effects. LIPUS is promising for clinical translation in protecting against MI/R injury. This will be great welfare for patients suffering from MI/R injury.