Aliskiren and valsartan mediate left ventricular remodeling post-myocardial infarction in mice through MMP-9 effects

J Mol Cell Cardiol. 2014 Jul:72:326-35. doi: 10.1016/j.yjmcc.2014.04.007. Epub 2014 Apr 23.

Abstract

We evaluated whether aliskiren, valsartan, or a combination of both was protective following myocardial infarction (MI) through effects on matrix metalloproteinase (MMP)-9. C57BL/6J wild type (WT, n=94) and MMP-9 null (null, n=85) mice were divided into 4 groups at 3h post-MI: saline (S), aliskiren (A; 50mg/kg/day), valsartan (V; 40mg/kg/day), or A+V and compared to no MI controls at 28days post-MI. All groups had similar infarct areas, and survival rates were higher in the null mice. The treatments influenced systolic function and hypertrophy index, as well as extracellular matrix (ECM) and inflammatory genes in the remote region, indicating that primary effects were on the viable myocardium. Saline treated WT mice showed increased end systolic and diastolic volumes and hypertrophy index, along with reduced ejection fraction. MMP-9 deletion improved LV function post-MI. Aliskiren attenuated the increase in end systolic volume and hypertrophy index, while valsartan improved end diastolic volumes and aliskiren+valsartan improved the hypertrophy index only when MMP-9 was absent. Extracellular matrix and inflammatory gene expression showed distinct patterns among the treatment groups, indicating a divergence in mechanisms of remodeling. This study shows that MMP-9 regulates aliskiren and valsartan effects in mice. These results in mice provide mechanistic insight to help translate these findings to post-MI patients.

Keywords: Aliskiren; Extracellular matrix; MMP-9; Myocardial infarction; Remodeling; Valsartan.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amides / pharmacology*
  • Animals
  • Antihypertensive Agents / pharmacology*
  • Drug Therapy, Combination
  • Extracellular Matrix / drug effects
  • Extracellular Matrix / enzymology
  • Female
  • Fumarates / pharmacology*
  • Gene Expression
  • Male
  • Matrix Metalloproteinase 9 / deficiency
  • Matrix Metalloproteinase 9 / genetics*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Myocardial Infarction / drug therapy*
  • Myocardial Infarction / enzymology
  • Myocardial Infarction / mortality
  • Myocardial Infarction / pathology
  • Myocardium / enzymology*
  • Myocardium / pathology
  • Stroke Volume / drug effects
  • Survival Analysis
  • Systole / drug effects
  • Tetrazoles / pharmacology*
  • Valine / analogs & derivatives*
  • Valine / pharmacology
  • Valsartan
  • Ventricular Function, Left / drug effects
  • Ventricular Remodeling / drug effects

Substances

  • Amides
  • Antihypertensive Agents
  • Fumarates
  • Tetrazoles
  • aliskiren
  • Valsartan
  • Matrix Metalloproteinase 9
  • Valine