Differential response of vascular hepatocyte growth factor concentration and lipid accumulation between telmisartan and losartan in ApoE-deficient mice

Abstract

Abstract. The favorable metabolic effects of telmisartan have been related to its blockade of angiotensin (Ang) II receptor and action as a partial agonist of peroxisome proliferatoractivated receptor γ (PPARγ). We designed a comparative study of telmisartan and losartan in ApoE-deficient mice. ApoE-deficient mice were fed a high-fat diet with or without telmisartan (10 mg/kg/day) or losartan (30 mg/kg/day) for 3 months. Treatment with telmisartan or losartan significantly reduced blood pressure, but did not affect serum cholesterol, triglyceride or glucose levels. Both drugs inhibited the development of lipid-rich plaque as assessed by oil red O staining. However, treatment with telmisartan, but not losartan, significantly improved endothelial dysfunction as assessed by the vasodilator response to acetylcholine. To elucidate the molecular mechanisms of the differential response in the improvement of endothelial dysfunction between telmisartan and losartan, we next focused on the expression of various cytokines. As both telmisartan and losartan attenuated interleukin-6 mRNA expression in the aorta, there was a significant change in endothelial nitric oxide synthase (eNOS) mRNA in the aorta. Notably, telmisartan, but not losartan, significantly increased the expression of hepatocyte growth factor (HGF), but not that of vascular endothelial growth factor (VEGF) in the aorta. Although a decrease in body weight and adipose tissue weight was observed with both telmisartan and losartan, liver weight was significantly decreased in only the telmisartan-treated group. Of importance, telmisartan markedly inhibited lipid accumulation in the liver. Overall, telmisartan and losartan induced differential responses in the improvement of endothelial dysfunction, probably due to their effects on vascular HGF levels and fatty liver. These favorable characteristics of telmisartan might be due to its action as a partial agonist of PPARγ, beyond its blood pressure-lowering effect, through Ang II blockade. IntroductionHigh blood pressure is closely associated with insulin resistance and dyslipidemia. Thus, current antihypertensive drugs should be designed to affect the cellular and biochemical mechanisms that contribute to an increase in blood pressure, and should also address the disordered lipid metabolism that often accompanies hypertension as part of the metabolic syndrome. Telmisartan, an angiotensin (Ang) type I receptor (AT1R) blocker (ARB), has been widely used in the treatment of hypertension and hypertension-related cardiovascular endorgan damage (1). When tested at concentrations that may be present in plasma with oral doses used for the treatment of hypertension, it was also identified as a unique moderately potent selective partial agonist of peroxisome proliferatoractivated receptor γ (PPARγ) (2,3).PPARγ plays an important role in regulating carbohydrate and lipid metabolism, and ligands for PPARγ can improve insulin sensitivity, reduce triglyceride (TG) levels and decrease the risk of atherosclerosis (4-6). A recent cl...

Improvement of metabolic syndrome by irbesartan via the PPARγ/HGF pathway in apolipoprotein E knockout mice

“…PPARγ has been reported to bind to the putative peroxisome proliferator response element (PPRE) in the promoter region of the HGF gene, resulting in an increase in HGF gene transcription, mRNA expression and protein secretion (9). Our group of investigators have reported that telmisartan (another PPARγ agonistic ARB), but not losartan (a classical ARB), improved endothelial dysfunction and fatty liver, due to an increased tissue HGF level (16). More directly, using AT1R KO mice, telmisartan, but not losartan, exhibited renal protective effects in a unilateral ureteral obstruction model (10).…”

Submaximal PPARγ activation and endothelial dysfunction: new perspectives for the management of cardiovascular disorders

“…A recent study confirmed that the vascular protective potential of telmisartan against diabetes mellitus‐associated VED and associated vascular complications is predominantly mediated through its partial PPARγ activating property (Toyama et al ., 2011). Telmisartan treatment of apolipoprotein E‐deficient mice fed a high‐fat diet was shown to significantly reduce blood pressure and considerably improve endothelial dysfunction (as assessed by the vasodilator response to acetylcholine) by modulating eNOS expression in the aorta; an effect that might be due to its action as a partial agonist of PPARγ (Nakagami et al ., 2008). Moreover, telmisartan was suggested to enhance the bioavailability and vascular generation of NO through a PPARγ‐mediated action (Ikejima et al ., 2008).…”

Evidence for the Benefits of Melatonin in Cardiovascular Disease

“…Cardiovascular pathology and AS have been observed to be associated with reduced local amounts of HGF in cardiac and vascular cells ( 398 – 400 ). Several drugs such as ARBs (angiotensin II receptor blockers) ( 400 – 402 ), ACEIs (angiotensin-converting-enzyme inhibitors) ( 399 , 400 , 403 ) and PPAR-γ agonists ( 404 ) have been shown to upregulated HGF, resulting in suppression of AS ( 402 , 405 ). Interestingly, melatonin has also been shown to upregulate HGF expression both in vitro ( 189 , 190 ) and in vivo ( 407 ).…”