The effects of different angiotensin II type 1 receptor blockers on the regulation of the ACE-AngII-AT1 and ACE2-Ang(1-7)-Mas axes in pressure overload-induced cardiac remodeling in male mice

J Mol Cell Cardiol. 2016 Aug;97:180-90. doi: 10.1016/j.yjmcc.2016.05.012. Epub 2016 May 19.

Abstract

Angiotensin II (AngII) type 1 receptor blockers (ARBs) have been effectively used in hypertension and cardiac remodeling. However, the differences among them are still unclear. We designed this study to examine and compare the effects of several ARBs widely used in clinics, including Olmesartan, Candesartan, Telmisartan, Losartan, Valsartan and Irbesartan, on the ACE-AngII-AT1 axis and the ACE2-Ang(1-7)-Mas axis during the development of cardiac remodeling after pressure overload. Although all of the six ARBs, attenuated the development of cardiac hypertrophy and heart failure induced by transverse aortic constriction (TAC) for 2 or 4weeks in the wild-type mice evaluated by echocardiography and hemodynamic measurements, the degree of attenuation by Olmesartan, Candesartan and Losartan tended to be larger than that of the other three drugs tested. Additionally, the degree of downregulation of the ACE-AngII-AT1 axis and upregulation of the ACE2-Ang(1-7)-Mas axis was higher in response to Olmesartan, Candesartan and Losartan administration in vivo and in vitro. Moreover, in angiotensinogen-knockdown mice, TAC-induced cardiac hypertrophy and heart failure were inhibited by Olmesartan, Candesartan and Losartan but not by Telmisartan, Valsartan and Irbesartan administration. Furthermore, only Olmesartan and Candesartan could downregulate the ACE-AngII-AT1 axis and upregulate the ACE2-Ang(1-7)-Mas axis in vitro. Our data suggest that Olmesartan, Candesartan and Losartan could effectively inhibit pressure overload-induced cardiac remodeling even when with knockdown of Ang II, possibly through upregulation of the expression of the ACE2-Ang(1-7)-Mas axis and downregulation of the expression of the ACE-AngII-AT1 axis. In contrast, Telmisartan, Valsartan and Irbesartan only played a role in the presence of AngII, and Losartan had no effect in the presence of AngII in vitro.

Keywords: Angiotensin II type 1-receptor blockers; Cardiac hypertrophy; Heart failure; Mechanical stretch; Pressure overload.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin II / deficiency
  • Angiotensin II / genetics
  • Angiotensin II / metabolism*
  • Angiotensin II Type 1 Receptor Blockers / administration & dosage
  • Angiotensin II Type 1 Receptor Blockers / pharmacology
  • Animals
  • Blood Pressure / drug effects
  • Cardiomegaly / etiology
  • Cardiomegaly / pathology
  • Cardiomegaly / physiopathology
  • Disease Models, Animal
  • Echocardiography
  • Hemodynamics / drug effects
  • Hypertension / complications
  • Hypertension / physiopathology
  • Male
  • Mice
  • Mice, Knockout
  • Myocardium / metabolism
  • Myocytes, Cardiac / drug effects
  • Myocytes, Cardiac / metabolism
  • Peptidyl-Dipeptidase A / metabolism*
  • Proto-Oncogene Proteins / metabolism*
  • RNA, Small Interfering / chemistry
  • Receptor, Angiotensin, Type 1 / metabolism*
  • Receptors, G-Protein-Coupled / metabolism*
  • Signal Transduction / drug effects*
  • Ventricular Remodeling / drug effects*

Substances

  • Angiotensin II Type 1 Receptor Blockers
  • Proto-Oncogene Proteins
  • RNA, Small Interfering
  • Receptor, Angiotensin, Type 1
  • Receptors, G-Protein-Coupled
  • proto-oncogene proteins c-mas-1
  • Angiotensin II
  • Peptidyl-Dipeptidase A