Vascular Smooth Muscle Cells Specific Deletion of Angiopoietin-Like Protein 8 Prevents AngII-Promoted Hypertension and Cardiovascular Hypertrophy.

Abstract

Angiopoietin-like protein 8 (ANGPTL8) plays important roles in lipid metabolism, glucose metabolism, inflammation, and cell proliferation and migration. Clinical studies have indicated that circulating ANGPTL8 concentrations are increased in patients with hypertension and positively associated with blood pressure. ANGPTL8 deficiency ameliorates blood pressure in mice treated with chronic intermittent hypoxia. Currently, little is known regarding the pathophysiological role of vascular smooth muscle cell (VSMC)-derived ANGPTL8 in hypertension and hypertensive cardiovascular remodelling. Circulating ANGPTL8 concentrations, as determined by enzyme-linked immunosorbent assay, were significantly higher in hypertensive patients than in controls (524.51 ± 26.97 vs 962.92 ± 15.91 pg/ml; P < 0.001). In hypertensive mice (angiotensin II [AngII] treatment for 14 days) and spontaneously hypertensive rats, ANGPTL8 expression was increased and predominantly located in VSMCs. In AngII-treated mice, systolic and diastolic blood pressure in Tagln-Cre-ANGPTL8fl/fl mice were approximately 15-25 mmHg lower than that in ANGPTL8fl/fl mice. AngII-induced vascular remodelling, vascular constriction, and increased expression of cell markers of proliferation (PCNA and Ki67) and migration (MMP-2 and MMP-9) were strikingly attenuated in Tagln-Cre-ANGPTL8fl/fl mice compared with ANGPTL8fl/fl mice. Furthermore, the AngII-induced increase in the heart size, heart weight, heart/body weight ratio, cardiomyocyte cross-sectional area, and collagen deposition was ameliorated in Tagln-Cre-ANGPTL8fl/fl mice compared with ANGPTL8fl/fl mice. In rat artery smooth muscle cells, ANGPTL8-short hairpin RNA decreased intracellular calcium levels and prevented AngII-induced proliferation and migration through the PI3K-Akt pathway, as shown using LY294002 (inhibitor of PI3K) and Akt inhibitor VIII. This study suggests that ANGPTL8 in VSMCs plays an important role in AngII-induced hypertension and associated cardiovascular remodelling. ANGPTL8 may be a novel therapeutic target against pathological hypertension and hypertensive cardiovascular hypertrophy. This study reveals a novel factor included in hypertension and hypertensive cardiovascular remodeling. We found that VSMC specific deletion of ANGPTL8 could lower blood pressure approximately15-25 mmHg. Besides its role in regulating blood pressure, ANGPTL8 knockout also attenuated cardiovascular remodeling and fibrosis in hypertensive mice. These new findings indicate that ANGPTL8 in VSMC is involved in the regulating of hypertension and associated cardiovascular hypertrophy, thus suggesting that ANGPTL8 might be a new therapeutic target for hypertension and hypertensive cardiovascular remodeling.