NH4Cl treatment prevents doxorubicin-induced myocardial dysfunction in vivo

Aims: Improvements in cancer treatment have significantly extended the lifespan of patients. However, due to the adverse effects of cancer treatment, cancer survivors are at increased risk of cardiovascular complications. Doxorubicin is a widely used spectrum antitumor drug, but the life-threatening side-effect of cardiotoxicity limits its clinical application. Ammonium chloride (NH4Cl), as a heteropolar compound with pH value regulation, can cause intracellular alkalization and metabolic acidosis thus effecting enzymatic activity and influencing the process of biological system. The underlying effect of NH4CL in DOX-induced cardiomyocyte apoptosis and hypertrophy in mice has never been reported before. Main methods: This study we used DOX to induce cardiac remodeling and dysfunction in mice. Myocardial histology was performed using HE staining. Myocardial cell size was measured by wheat germ agglutinin (WGA) staining. Echocardiographic evaluation of cardiac function, qPCR detection of the mRNA expression of cardiac hypertrophy and inflammation markers. Apoptosis was detected by TUNEL method. Transmission electron microscopy (TEM) was used to detect autophagy. Key findings: We found that NH4CL effectively improved DOX-induced cardiomyocyte apoptosis and cardiac dysfunction in mice. Our results showed that NH4CL significantly improved DOX-induced contractile dysfunction, inflammation, apoptosis and autophagy in mice. Significance: Our results indicate that NH4CL is effective in improving DOX-induced cardiac dysfunction and remodeling. It may therefore be a therapeutic entry point to limit doxorubicin-mediated adverse cardiac reactions.