Telmisartan acts through the modulation of ACE-2/ANG 1-7/mas receptor in rats with dilated cardiomyopathy induced by experimental autoimmune myocarditis

Life Sci. 2012 Feb 13;90(7-8):289-300. doi: 10.1016/j.lfs.2011.11.018. Epub 2011 Dec 19.

Abstract

Aim: Recent findings have suggested that a therapeutic approach to amplify or stimulate the angiotensin-converting enzyme-2 [ACE-2]-angiotensin 1-7 [ANG 1-7] mas axis could provide protection against the development of cardiovascular diseases. We investigated the cardioprotective effects of telmisartan in rats with dilated cardiomyopathy [DCM] after experimental autoimmune myocarditis [EAM].

Main methods: DCM was elicited in Lewis rats by immunization with cardiac myosin, and twenty-eight days after immunization, the surviving Lewis rats were divided into two groups and treated with either telmisartan (10mg/kg/day) or vehicle.

Key findings: Telmisartan treatment effectively suppressed myocardial protein and mRNA expressions of inflammatory markers [CD68, iNOS, NF-kB, interleukin-1β, interferon-γ, monocyte chemotactic protein-1] in comparison to vehicle-treated rats. In contrast, myocardial protein levels of ACE-2 and ANG 1-7 mas receptor were upregulated in the telmisartan-treated group compared with vehicle-treated rats. Telmisartan treatment significantly reduced fibrosis and hypertrophy and their marker molecules [OPN, CTGF, TGF-β1 and collagens I and III and atrial natriuretic peptide and GATA-4, respectively] compared with those of vehicle-treated rats. In addition, telmisartan treatment significantly lowered the protein expressions of NADPH oxidase subunits p47phox, p67phox, and superoxide production when compared with vehicle-treated rats. Telmisartan treatment significantly decreased the expression levels of mitogen-activated protein kinase (MAPK) signaling molecules than with those of vehicle-treated rats. Also, telmisartan treatment significantly improved LV systolic and diastolic function.

Significance: These results indicate that telmisartan treatment significantly improved LV function and ameliorated the progression of cardiac remodeling through the modulation of ACE-2/ANG 1-7/Mas receptor axis in rats with DCM after EAM.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin-Converting Enzyme 2
  • Animals
  • Antihypertensive Agents / pharmacology
  • Benzimidazoles / pharmacology*
  • Benzimidazoles / therapeutic use
  • Benzoates / pharmacology*
  • Benzoates / therapeutic use
  • Blotting, Western
  • Cardiomyopathy, Dilated / drug therapy
  • Cardiomyopathy, Dilated / etiology*
  • Cardiomyopathy, Dilated / pathology*
  • Disease Models, Animal
  • Enzyme-Linked Immunosorbent Assay
  • Fluorescent Antibody Technique
  • Gene Expression Regulation / drug effects*
  • Male
  • Myocarditis / complications*
  • Myocarditis / drug therapy
  • Nervous System Autoimmune Disease, Experimental / complications
  • Peptidyl-Dipeptidase A / blood
  • Peptidyl-Dipeptidase A / metabolism*
  • Proto-Oncogene Proteins / blood
  • Proto-Oncogene Proteins / metabolism*
  • Rats
  • Rats, Inbred Lew
  • Real-Time Polymerase Chain Reaction
  • Receptors, G-Protein-Coupled / blood
  • Receptors, G-Protein-Coupled / metabolism*
  • Superoxides / chemistry
  • Telmisartan

Substances

  • Antihypertensive Agents
  • Benzimidazoles
  • Benzoates
  • Proto-Oncogene Proteins
  • Receptors, G-Protein-Coupled
  • proto-oncogene proteins c-mas-1
  • Superoxides
  • Peptidyl-Dipeptidase A
  • Ace2 protein, rat
  • Angiotensin-Converting Enzyme 2
  • Telmisartan