Breast cancer susceptibility gene 2 upregulation alleviated cardiac hypertrophy in angiotensin II-treated mice

TL;DR

Increasing BRCA2 levels in mice reduced heart enlargement caused by angiotensin II, likely by reducing inflammation and cell death.

Contribution

This study shows that upregulating BRCA2 can alleviate hypertrophic cardiomyopathy by reducing inflammation and apoptosis.

Findings

BRCA2 overexpression attenuated cardiac hypertrophy in angiotensin II-treated mice.

BRCA2 upregulation reduced myocardial inflammation and apoptotic markers in hypertrophic cardiomyopathy.

Cardiac fibrosis was significantly reduced with BRCA2 upregulation in the disease model.

Abstract

Loss of breast cancer susceptibility gene 2 (BRCA2) function was found to exacerbate doxorubicin-mediated cardiomyocyte apoptosis and promote heart failure progression. We hypothesized that upregulation of BRCA2 may alleviate hypertrophic cardiomyopathy. Hypertrophic cardiomyopathy was established in mice via chronic angiotensin II (Ang II) administration (1.44 mg/kg/day) using osmotic minipumps. Cardiac BRCA2 expression was significantly downregulated in Ang II-treated mice. Cardiac hypertrophy triggered by Ang II in mice was significantly attenuated upon BRCA2 overexpression. Similarly, in cultured primary cardiomyocytes, Ang II-induced hypertrophic responses were suppressed by BRCA2 upregulation. The cardiac fibrosis was significantly attenuated after upregulation of BRCA2 in Ang II-induced hypertrophic cardiomyopathy. The myocardial inflammatory response to Ang II, characterized by elevated interleukin (IL)-1β, IL-6, and tumor necrosis factor alpha (TNF-α) levels, was markedly reduced with BRCA2 overexpression. The apoptotic biomarkers including Bax and cleaved caspase 3 (CC3) increased in the heart of hypertrophic cardiomyopathy, and attenuated after upregulation of BRCA2. These results indicated that upregulation of BRCA2 could improve hypertrophic cardiomyopathy. BRCA2 alleviated cardiac hypertrophy via attenuation of inflammation and apoptosis.

•BRCA2 expression was reduced in hypertrophic cardiomyopathy.•Upregulation of BRCA2 could improve hypertrophic cardiomyopathy.•BRCA2 attenuated hypertrophic cardiomyopathy through inhibition of inflammation and apoptosis.

BRCA2 expression was reduced in hypertrophic cardiomyopathy.

Upregulation of BRCA2 could improve hypertrophic cardiomyopathy.

BRCA2 attenuated hypertrophic cardiomyopathy through inhibition of inflammation and apoptosis.

Figures