Effects Of Telmisartan On Vascular Remodeling In Hypertension And Its Molecular Mechanism

Objective: To investigate the effects of Telmisartan on vascular expression of angiotensin-converting enzyme 2 (ACE2), Profilin-1 in spontaneous hypertension rats (SHR) and vascular smooth muscle cells (VSMC) cultured in vitro, and to explore the regulatory roles and relevant mechanisms of Telmisartan in vascular fibrosis, extracellular matrix (ECM) generation and vascular hypertrophy and remodeling by combination of the vascular morphology and function.Methods: 10-week SHR and Wistar-Kyoto (WKY) rats were treated with telmisartan (5 or 10 mg·kg^-1·d^-1) or placebo for 10 weeks. Systolic blood pressure of rat was measured by tail-cuff method. Vascular morphology and collagen content were analyzed by light microscope, transmission electron microscope (TEM) and picric acid-sirius red (PSR) staining, respectively. The cultured human umbilical arterial smooth muscle cells (HUASMC) were stimulated by Ang II in the presence and absence of Telmisartan (1μM or 10μM). The mRNA, protein and phosphorylation levels of ACE2, Profilin-1, extracellular regulated kinase (ERK1/2) and p38 mitogen-activated protein kinase (MAPK) were determined with real-time PCR and Western blotting in aorta of treated rats and cultured HUASMC.Results: Compared with WKY rats, there were significantly elevated systolic blood pressures and impaired vascular structure of aorta with higher ratio of media thickness (MT) and luminal internal diameter (LD) as well as upregulation of collagen distribution in SHR, accompanied by depressed expression of ACE2 and enhanced expression of Profilin-1, and collagen I (P<0.05, respectively). Treatment with Telmisartan reduced the blood pressure and improved remarkably vascular structure in SHR rats, along with an increase in ACE2 expression and marked reductions in the ratio of MT/LD and expressions of Profilin-1, collagen I as well as phosphorylation levels of ERK1/2 (P<0.05, respectively). There were no significant differences in collagen III expression of aorta among groups (P<0.05, respectively). In cultured HUASMC, exposure of cells to Ang II resulted in a dose-dependent increase in mRNA and protein levels of Profilin-1, especially in 100 nM concentration (P<0.05). In addition, there were depressed mRNA expression of ACE2 and upregulated phosphorylation levels of ERK1/2 (P<0.05, respectively). Treatment with Telmisartan (1μM and 10μM) reversed strikingly Ang II-induced upregulation of Profilin-1 mRNA and protein levels, accompanied by enhancement of ACE2 mRNA expression and decrease in ERK1/2 phosphorylation levels (P<0.05, respectively). Conclusion: Chronic Telmisartan treatment strikingly improves vascular hypertrophy and remodeling as well as structure injury in SHR. These vascular protective effects of Telmisartan may be associated with the regulation in the vascular expression of ACE2 and Profilin-1 and ERK phosphorylation signaling pathway. The various ways to intervene the expressions and activities of ACE2 and Profilin-1 may become new approaches to prevent and treat vascular remodeling-related diseases such as hypertension.