SH3-containing guanine nucleotide exchange factor (SGEF) ameliorates pressure overload induced cardiac hypertrophy via enhancing EGFR-NRF2 mediated ferroptosis inhibition.

SH3-containing guanine nucleotide exchange factor (SGEF) is reportedly associated with tumorigenesis. However, the role of SGEF in cardiovascular diseases such as cardiac hypertrophy has not been elucidated. Here, we used a pressure overload-induced cardiac hypertrophy mouse model to explore the role and underlying mechanism of SGEF in pathological cardiac hypertrophy. Adeno-associated virus 9 (AAV9) was used to deliver SGEF and shSGEF to mouse hearts to induce cardiac overexpression or knockdown of SGEF. The mice were then subjected to aortic banding surgery to establish a pathological cardiac hypertrophy model. Echocardiography was performed at 4 weeks postsurgery to evaluate cardiac function. Cardiomyocytes were stimulated with angiotensin II to establish an in vitro model. We found that SGEF was downregulated in heart tissue at 4 weeks after aortic banding (AB) and in cardiomyocytes stimulated with angiotensin II. These results show that SGEF overexpression ameliorates pressure overload-induced cardiac hypertrophy, fibrosis and dysfunction, while SGEF knockdown exacerbates pressure overload-induced cardiac hypertrophy, fibrosis and dysfunction. Moreover, SGEF overexpression relieved, whereas SGEF knockdown aggravated, cardiac oxidative stress and ferroptosis, which was confirmed by an in vitro study. Mechanistically, we found that SGEF enhanced the stability of epidermal growth factor receptor (EGFR), inhibited its ubiquitination and subsequently promoted downstream nuclear factor erythroid 2-related factor 2 (NRF2) activation, thus inhibiting ferroptosis. When we used the EGFR inhibitor osimertinib, the protective effect of SGEF on pathological cardiac hypertrophy was counteracted. Taken together, these findings indicate that SGEF protects against pressure overload-induced cardiac hypertrophy, fibrosis and dysfunction by enhancing EGFR-NRF2 signaling-mediated ferroptosis inhibition. Targeting SGE has therapeutic potential for preventing pathological cardiac hypertrophy leading to heart failure.