Cardioprotective Effects of Telmisartan against Heart Failure in Rats Induced By Experimental Autoimmune Myocarditis through the Modulation of Angiotensin-Converting Enzyme-2/Angiotensin 1-7/Mas Receptor Axis

Abstract

Angiotensin-converting enzyme-2 (ACE-2) is a homolog of ACE that preferentially forms angiotensin-(ANG)-1-7 from angiotensin II (ANG II). We investigated the cardioprotective effects of telmisartan, a well-known angiotensin receptor blockers (ARBs) against experimental autoimmune myocarditis (EAM). EAM was induced in Lewis rats by immunization with porcine cardiac myosin. The rats were divided into two groups and treated with telmisartan (10 mg/kg/day) or vehicle for 21 days. Myocardial functional parameters were significantly improved by treatment with telmisartan compared with vehicle-treated rats. Telmisartan lowered myocardial protein expressions of NADPH oxidase subunits 3-nitrotyrosine, p47phox, p67 phox, Nox-4 and superoxide production significantly than vehicle-treated rats. In contrast myocardial protein levels of ACE-2, ANG 1-7 mas receptor were upregulated in the telmisartan treated group compared with those of vehicle-treated rats. The myocardial protein expression levels of tumor necrosis factor receptor (TNFR)-associated factor (TRAF)-2, C/EBP homologous protein (CHOP) and glucose-regulated protein (GRP) 78 were decreased in the telmisartan treated rats compared with those of vehicle-treated rats. In addition, telmisartan treatment significantly decreased the protein expression levels of phospho-p38 mitogen-activated protein kinase (MAPK), phospho-JNK, phospho-ERK and phospho (MAPK) activated protein kinase-2 than with those of vehicle-treated rats. Moreover, telmisartan significantly decreased the production of proinflammatory cytokines, myocardial apoptotic markers and caspase-3 positive cells compared with those of vehicle-treated rats. Therefore, we suggest that telmisartan was beneficial protection against heart failure in rats, at least in part by suppressing inflammation, oxidative stress, ER stress as well as signaling pathways through the modulation of ACE2/ANG1-7/Mas receptor axis.

Angiotensin-Converting Enzyme 2 (ACE2) Activator Diminazene Aceturate Ameliorates Endotoxin-Induced Uveitis in Mice

“…39,53,54 Moreover, it is significant for providing a potential strategy to enhance the protective axis for treatment of ocular inflammatory diseases. In particular, the prolonged inflammation often results in a chronic inflammatory condition, which is the major pathogenic mechanism in a number of autoimmune diseases, such as rheumatoid arthritis as well as uveitis.…”

Effects of telmisartan and linagliptin when used in combination on blood pressure and oxidative stress in rats with 2-kidney-1-clip hypertension

“…As patients with diabetes often suffer from metabolic syndrome including hypertension, the influence of DPP-4 inhibitors on BP is particularly important and until now, it is not defined. There is some controversy about the role DPP-4 and its inhibition has on BP control, being involved in pathways that can both increase [20] and decrease [22] SBP.…”

“…Used in the treatment of cardiac failure, ARBs and ACE inhibitors reduce the impact of angiotensin I-mediated effects such as oxidative stress, inflammation and LDL cholesterol trafficking, establishing a prothrombotic state [18]. The attenuation of oxidative stress by ARBs and ACE inhibitors in experimental models is well established in scientific literature [19,20]. In addition, these agents prevent myocardial fibrosis and decrease leftventricular stiffness during the progression of chronic heart failure [21,22].…”

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“…NF-kB, iNOS. In addition, ARBs enhance the anti-inflammatory cytokines (37,38). Ang 1-7 directly blunts the Ang IIinduced activation of pro-inflammatory signalling in kidney cells.…”