Angiotensin II mediates hypertensive cardiac fibrosis via an Erbb4-IR-dependent mechanism

Transforming growth factor b (TGF-b)/Smad3 plays a vital role in hypertensive cardiac fibrosis. The long non-coding RNA (lncRNA) Erbb4-IR is a novel Smad3-dependent lncRNA that mediates kidney fibrosis. However, the role of Erbb4-IR in hypertensive heart disease remains unexplored and was investi-gated in the present study by ultrasound-microbubble-medi-ated silencing of cardiac Erbb4-IR in hypertensive mice induced by angiotensin II. We found that chronic angiotensin II infu-sion induced hypertension and upregulated cardiac Erbb4-IR, which was associated with cardiac dysfunction, including a decrease in left ventricle ejection fraction (LVEF) and LV frac-tional shortening (LVFS) and an increase in LV mass. Knock -down of cardiac Erbb4-IR by Erbb4-IR short hairpin RNA (shRNA) gene transfer effectively improved the angiotensin II-induced deterioration of cardiac function, although blood pressure was not altered. Furthermore, silencing cardiac Erbb4-IR also inhibited angiotensin II-induced progressive car-diac fibrosis, as evidenced by reduced collagen I and III, alpha-smooth muscle actin (a-SMA), and fibronectin accumulation. Mechanistically, improved hypertensive cardiac injury by specifically silencing cardiac Erbb4-IR was associated with increased myocardial Smad7 and miR-29b, revealing that Erbb4-IR may target Smad7 and miR-29b to mediate angio-tensin II-induced hypertensive cardiac fibrosis. In conclusion, Erbb4-IR is pathogenic in angiotensin II (Ang II)-induced car-diac remodeling, and targeting Erbb4-IR may be a novel ther-apy for hypertensive cardiovascular diseases.

Automated summary

This study investigated the role of Erbb4-IR in hypertensive heart disease using ultrasound-microbubble-mediated silencing. It was found that Erbb4-IR mediates cardiac fibrosis induced by Ang II, and silencing Erbb4-IR effectively improves cardiac dysfunction and fibrosis. Therefore, targeting Erbb4-IR may be a novel therapy for hypertensive cardiovascular diseases.