Aliskiren and valsartan mediate left ventricular remodeling post-myocardial infarction in mice through MMP-9 effects.
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.
San Antonio Cardiovascular Proteomics Center and Mississippi Center for Heart Research, Department of Biophysics and Physiology, University of Mississippi Medical Center, Jackson, MS, USA.
Trevi A
TA
Ramirez
San Antonio Cardiovascular Proteomics Center and Mississippi Center for Heart Research, Department of Biophysics and Physiology, University of Mississippi Medical Center, Jackson, MS, USA.
Rugmani Padmanabhan
RP
Iyer
San Antonio Cardiovascular Proteomics Center and Mississippi Center for Heart Research, Department of Biophysics and Physiology, University of Mississippi Medical Center, Jackson, MS, USA; Department of Electrical and Computer Engineering, University of Texas at San Antonio, San Antonio, TX, USA.
Omid
O
Ghasemi
San Antonio Cardiovascular Proteomics Center and Mississippi Center for Heart Research, Department of Biophysics and Physiology, University of Mississippi Medical Center, Jackson, MS, USA.
Elizabeth F
EF
Lopez
San Antonio Cardiovascular Proteomics Center and Mississippi Center for Heart Research, Department of Biophysics and Physiology, University of Mississippi Medical Center, Jackson, MS, USA.
Daniel B
DB
Levin
San Antonio Cardiovascular Proteomics Center and Mississippi Center for Heart Research, Department of Biophysics and Physiology, University of Mississippi Medical Center, Jackson, MS, USA.
Jianhua
J
Zhang
San Antonio Cardiovascular Proteomics Center and Mississippi Center for Heart Research, Department of Biophysics and Physiology, University of Mississippi Medical Center, Jackson, MS, USA.
Rogelio
R
Zamilpa
San Antonio Cardiovascular Proteomics Center and Mississippi Center for Heart Research, Department of Biophysics and Physiology, University of Mississippi Medical Center, Jackson, MS, USA; Department of Mathematics, University of Texas at San Antonio, San Antonio, TX, USA.
Youn-Min
YM
Chou
San Antonio Cardiovascular Proteomics Center and Mississippi Center for Heart Research, Department of Biophysics and Physiology, University of Mississippi Medical Center, Jackson, MS, USA; Department of Electrical and Computer Engineering, University of Texas at San Antonio, San Antonio, TX, USA.
Yu-Fang
YF
Jin
San Antonio Cardiovascular Proteomics Center and Mississippi Center for Heart Research, Department of Biophysics and Physiology, University of Mississippi Medical Center, Jackson, MS, USA; Research Service, G.V. (Sonny) Montgomery Veterans Affairs Medical Center, Jackson, MS, USA. Electronic address: mllindsey@umc.edu.
Merry L
ML
Lindsey
D000577:Amides / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D004359:Drug Therapy, Combination; D005109:Extracellular Matrix / Q000187:drug effects / Q000201:enzymology; D005260:Female; D005650:Fumarates / Q000494:pharmacology*; D015870:Gene Expression; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000172:deficiency / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000201:enzymology / Q000401:mortality / Q000473:pathology; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D013318:Stroke Volume / Q000187:drug effects; D016019:Survival Analysis; D013599:Systole / Q000187:drug effects; D013777:Tetrazoles / Q000494:pharmacology*; D014633:Valine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000068756:Valsartan; D016277:Ventricular Function, Left / Q000187:drug effects; D020257:Ventricular Remodeling / Q000187:drug effects
D000577:Amides; D000959:Antihypertensive Agents; D005650:Fumarates; D013777:Tetrazoles; C446481:aliskiren; D000068756:Valsartan; D020780:Matrix Metalloproteinase 9; D014633:Valine
Aliskiren; Extracellular matrix; MMP-9; Myocardial infarction; Remodeling; Valsartan