Reduced expression of transmembrane protein 43 during cardiac hypertrophy leads to worsening heart failure in mice.

Abstract

Transmembrane protein 43 (TMEM43), a member of the transmembrane protein subfamily, was found to be associated with arrhythmogenic right ventricular cardiomyopathy. However, its role in cardiac hypertrophy has not been elucidated. Here, we used a pressure overload-induced cardiac hypertrophy model to explore the role of TMEM43 in heart failure. Mice were subjected to aortic banding (AB) to induce cardiac hypertrophy. The mice were also randomly selected to receive injection of adeno-associated virus 9 (AAV9)-shTMEM43 to knockdown TMEM43 in cardiomyocytes or control AAV9 (ScRNA). Four weeks after AB, the mice were subjected to echocardiography to evaluate cardiac function. Neonatal rat cardiomyocytes (NRCMs) were stimulated with angiotensin II (AngII, 1 μM) and transfected with an adenovirus to over-express TMEM43. We found that TMEM43 was downregulated in mouse hearts and cardiomyocytes poststimulation. Mice with TMEM43 knockdown showed worsening heart failure accompanied by deteriorating cardiac function and exacerbated cardiac hypertrophy and fibrosis at 4 weeks post-AB. NRCMs over-expressing TMEM43 exhibited an ameliorated hypertrophic response. Moreover, we found that TMEM43 deficiency increased nuclear factor kappa B (NF-κB) activation in mouse hearts post-AB, while TMEM43 over-expression reduced NF-κB activation in cardiomyocytes upon AngII stimulation. Thus, we conclude that reduced expression of TMEM43 during cardiac hypertrophy leads to worsening heart failure in mice.