Telmisartan, a unique ARB, improves left ventricular remodeling of infarcted heart by activating PPAR gamma

Abstract

Unfavorable left ventricular (LV) remodeling after myocardial infarction (MI) leads to cardiac dysfunction. We examined whether Telmisartan, an angiotensin (Ang) II type I receptor blocker (ARB), could improve the recovery of LV function in a rat model of MI. The effect of Telmisartan as a peroxisome proliferator-activated receptor-g (PPAR-g) agonist was also investigated. After 28 days of MI, a significant improvement of survival was observed in the Telmisartan-treated rat group compared with the vehicle control rat group, non-PPAR-g agonistic ARB (Losartan)-treated rat group, and Telmisartan plus specific PPAR-g antagonist (GW9662)-treated rat group. Although no significant differences of blood pressure or infarct size were observed among these four groups, the Telmisartan group had better systolic and diastolic LV function. There was a significant reduction of the plasma brain natriuretic peptide level, cardiac fibrosis area, infiltration of macrophages, size of cardiomyocytes, terminal deoxynucleotidyl transferase dUTP nick end labeling-positive myocytes, activation of matrix metalloproteinases-2 and -9 (MMPs-2/9), and expression of transforming growth factor b-1 (TGF-b1), connective tissue growth factor (CTGF), and osteopontin (OPN), while expression of PPAR-g and activation of tissue inhibitor of metalloproteinase-1 (TIMP-1) was enhanced, in the noninfarcted myocardium of rats from the Telmisartan group compared with the other three groups. To mimic ischemic conditions in vitro, neonatal rat cardiomyocytes and cardiac fibroblasts were incubated in hypoxic condition for 24 h. Increased transcriptional activation of PPAR-g and TIMP-1, and inhibition of TGF-b1 expression were observed in cardiomyocytes, while decreased activation of MMPs-2/9 and decrease in CTGF and OPN expression was seen in cardiac fibroblasts cultured with Telmisartan. In conclusion, Telmisartan prevented unfavorable cardiac remodeling through a reduction of cardiac hypertrophy and fibrosis. An anti-inflammatory effect and PPAR-g activation were suggested to be important in addition to suppression of Ang II activity. Unfavorable left ventricular (LV) remodeling after myocardial infarction (MI) is characterized by hypertrophy associated with interstitial fibrosis of the noninfarcted myocardium, and causes LV dilatation and cardiac dysfunction. It is known that angiotensin II (Ang II) has a crucial role in the development of unfavorable LV remodeling, and recent studies based on animal experiments have demonstrated that treatment with an Ang-converting enzyme inhibitor (ACE-I) and/or Ang II type I receptor blocker (ARB) can attenuate unfavorable LV remodeling. 1,2 Moreover, other experimental studies suggested that activation of peroxisome proliferator-activated receptor-g (PPAR-g), a transcription factor, improves unfavorable LV remodeling after MI. [3][4][5] PPAR-g agonists not only regulate insulin sensitivity, but also have an anti-inflammatory effect by inhibiting the expression of adhesion molecules, cytokines, and chemokines, as well ...

Triple drug combination of telmisartan, amlodipine and hydrochlorothiazide in the treatment of essential hypertension

“…Apart from effective BP lowering, telmisartan is also associated with renal protection, improved ventricular remodelling, reduced inflammation and oxidative stress, etc. [7][8][9][10]. Many authors have demonstrated the superiority of telmisartan when combined with other antihypertensives like amlodipine or HCT compared to monotherapy.…”

The Inhibitory Effect of Telmisartan on the Metabolism of Arachidonic Acid by CYP2C9 and CYP2C8: An <i>in Vitro</i> Study

“…1,2) Telmisartan, one of the angiotensin II receptor blockers (ARBs), is known to prevent cardiovascular events by reducing blood pressure 18) and to improve left ventricular remodeling induced by myocardial infarction (MI). 19) However, several patients have experienced side effects while taking telmisartan, including MI at a rate of 39/2036 (1.9%) and angina pectoris at a rate of 18/2036 (0.9%) (http://www.ehealthme.com/ drug/telmisartan/; accessed January 14, 2017).…”

Telmisartan Protects against Vascular Dysfunction with Peroxisome Proliferator-Activated Receptor-&#947; Activation in Hypertensive 5/6 Nephrectomized Rats

“…Other reports also showed that telmisartan was more effective in ameliorating coronary arterial remodeling and cardiac fibrosis and inflammation than losartan in a mouse model of obesity and type 2 diabetes and a rat model of myocardial infarction [23,24]. In addition to these studies, our previous report compared the effects of telmisartan with the same dose of ARBs including losartan [16].…”