Transforming growth factor β (TGF-β)/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 investigated in the present study by ultrasound-microbubble-mediated silencing of cardiac in hypertensive mice induced by angiotensin II. We found that chronic angiotensin II infusion induced hypertension and upregulated cardiac , which was associated with cardiac dysfunction, including a decrease in left ventricle ejection fraction (LVEF) and LV fractional shortening (LVFS) and an increase in LV mass. Knockdown of cardiac by 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 also inhibited angiotensin II-induced progressive cardiac fibrosis, as evidenced by reduced collagen I and III, alpha-smooth muscle actin (α-SMA), and fibronectin accumulation. Mechanistically, improved hypertensive cardiac injury by specifically silencing cardiac was associated with increased myocardial and , revealing that may target and to mediate angiotensin II-induced hypertensive cardiac fibrosis. In conclusion, is pathogenic in angiotensin II (Ang II)-induced cardiac remodeling, and targeting may be a novel therapy for hypertensive cardiovascular diseases.