Atorvastatin and sildenafil decrease vascular TGF-β levels and MMP-2 activity and ameliorate arterial remodeling in a model of renovascular hypertension

Abstract

Imbalanced matrix metalloproteinase (MMP)-2 activity and transforming growth factor expression (TGF-β) are involved in vascular remodeling of hypertension. Atorvastatin and sildenafil exert antioxidant and pleiotropic effects that may result in cardiovascular protection. We hypothesized that atorvastatin and sildenafil alone or in association exert antiproliferative effects by down-regulating MMP-2 and TGF-β, thus reducing the vascular hypertrophy induced by two kidney, one clip (2K1C) hypertension.Sham and 2K1C rats were treated with oral atorvastatin 50 mg/kg, sildenafil 45 mg/kg, or both, daily for 8 weeks. Blood pressure was monitored weekly. Morphologic changes in the aortas were studied. TGF-β levels were determined by immunofluorescence. MMP-2 activity and expression were determined by in situ zymography, gel zymography, Western blotting, and immunofluorescence. The effects of both drugs on proliferative responses of aortic smooth muscle cells to PDGF and on on MMP-2 activity in vitro were determined. Atorvastatin, sildenafil, or both drugs exerted antiproliferative effects in vitro. All treatments attenuated 2K1C-induced hypertension and prevented the increases in the aortic cross-sectional area and media/lumen ratio in 2K1C rats. Aortas from 2K1C rats showed higher collagen deposition, TGF-β levels and MMP-2 activity and expression when compared with Sham-operated animals. Treatment with atorvastatin and/or sildenafil was associated with attenuation of 2K1C hypertension-induced increases in these pro-fibrotic factors. However, these drugs had no in vitro effects on hr-MMP-2 activity.Atorvastatin and sildenafil was associated with decreased vascular TGF-β levels and MMP-2 activity in renovascular hypertensive rats, thus ameliorating the vascular remodeling. These novel pleiotropic effects of both drugs may translate into protective effects in patients.

Sildenafil Citrate Influences Production of TNF-α in Healthy Men Lymphocytes

“…Researchers did not observe the effect of SC on IL-10 production which is in line with our results [28]. Interestingly, studies performed by Guimaraes et al showed that treatment with sildenafil was associated with decreased vascular TGF-β level in renovascular hypertensive rats which confirm the tendency that we observed in our research [29].…”

microRNA and Metabolite Signatures Linked to Early Consequences of Lethal Radiation

“…A recent study exploring the cardiac atrophy caused by lethal radiation underscored the key role of the TGF-beta signal in heart fibrosis, metabolic disordering, and impaired contractility 59 . Supporting this evidence we found two TGF-beta-associated molecules, namely, miR-17-5p 60 and sildenafil 61 , differentially expressed during the Early phase post-TBI.…”

Atorvastatin, Losartan and Captopril Lead to Upregulation of TGF-β, and Downregulation of IL-6 in Coronary Artery Disease and Hypertension

“…It is well known that cytokines can manipulate cardiovascular system, like the roles played by TNF-α in the infectious shock [8], it has been hypothesized that cytokines may participate in the induction of hypertension. Previous investigations also confirm that serum levels of IL-6, IL-8, TGF-β and TNF-α were altered in the patients suffering from hypertension and CAD [9, 10]. Aspirin, Clopidogrel, Atorvastatin, Betablokers (Metoprolol and Carvedilol), Nitrates, Losartan and Captopril are the main drug components that are used for treatment of hypertension and CAD [11–13].…”

“…Moreover, since the significant relations between nerve/cardiovascular systems with immune system via cytokines network were also reported by investigators [31], based on the results presented in the current study it could be assumed that Atorvastatin, Losartan and Captopril, in addition to the known mechanisms, may improve hypertension and CAD via downregulation of pro-inflammatory cytokine and upregulation of anti-inflammatory cytokines, as indirect pathways, and this hypothesis need to be evaluated with more experimental and clinical trial studies. Interestingly, there is a report by Guimarães et al, which showed that Atorvastatin downregulates TGF-β [9]. It appears that the drugs show various features when they are used alone or in combination with other components.…”