What is the clinical evidence from this study?

Study design: Other. Population: Chronic volume overload-induced heart failure (n=24). Intervention: Targeted deletion of MMP-9 (MMP-9 knockout) vs. Wild type (WT) mice. Primary outcome: Endocardial endothelial-myocyte coupling (relaxation to acetylcholine and nitroprusside) (p=<0.05).

January 1, 2008Open Access

Targeted deletion of MMP-9 attenuates myocardial contractile dysfunction in heart failure

Q: What are the key findings of this study?

Targeted deletion of the MMP-9 gene significantly restored endocardial endothelial-myocyte coupling and attenuated myocardial contractile dysfunction in mice with chronic volume overload.

KMKS MoshalUniversity of Louisville WRWE RodriguezUniversity of Louisville USUtsav SenIcahn School of Medicine at Mount Sinai

Key Result

Targeted deletion of the MMP-9 gene significantly restored endocardial endothelial-myocyte coupling and attenuated myocardial contractile dysfunction in mice with chronic volume overload.

Structured PICO

Does targeted deletion of MMP-9 prevent endocardial endothelial-myocyte uncoupling and myocardial contractile dysfunction in a mouse model of chronic volume overload?

Population

24 eight- to ten-week-old male wild-type and MMP-9 knockout mice subjected to arteriovenous fistula to induce chronic volume overload and followed for 8-10 weeks.

Intervention

Targeted deletion of MMP-9 (MMP-9 knockout)

Comparator

Wild type (WT) mice with AVF, and sham-operated mice as controls

Outcome

Endocardial endothelial-myocyte (EM) functions (responses to acetylcholine, nitroprusside, and bradykinin) and MMP-9 activitysurrogate

Targeted deletion of MMP-9 restores endocardial endothelial-myocyte coupling in a mouse model of chronic volume overload, suggesting MMP-9 activation causes EM uncoupling and myocardial contractile dysfunction.

Main Result

p-value: p=<0.05

Limitations

Animal model findings may not directly translate to human heart failure.
The exact mechanisms of synergism between different MMPs (e.g., MMP-2 and MMP-9) remain to be fully elucidated.

Abstract

Chronic volume overload (VO) on the left ventricle (LV) augments redox stress and activates matrix metalloproteinase (MMP) which causes the endocardial endothelial-myocyte (EM) disconnection leading to myocardial contractile dysfunction. VO-induced MMP-9 activation impairs cardiac functions, in part by endothelial endocardial apoptosis, but the role of MMP-9 on EM functions remains obscure. We conjecture that chronic VO activates MMP-9 and causes EM uncoupling. Arteriovenous fistula (AVF) was created in genetically identical wild type (WT) mice (FVB/NJ) and MMP-9 knockout mice (MMP-9KO, FVB.Cg-MMP9(tm1Tvu)/J). Sham-operated mice were used as controls. Before experimentation the phenotype analysis of MMP-9KO mice was carried out. In-gel-gelatin zymography for MMP-9 activation was performed on LV homogenates. The EM functions were determined on LV rings using tissue myobath. We report a decrease in MMP-9 activity in left ventricular myocardial extracts in MMP-9 deficient mice after AVF. The responses to drugs affecting cardiac functions (acetylcholine (Ach), nitroprusside and bradykinin) were attenuated in AVF mice suggesting the impairment of EM coupling. Interestingly, the EM functions were restored in the MMP-9 deficient mice after AVF. We suggest a direct cause-and-effect relationship between MMP-9 activation and EM uncoupling in LV myocardium after chronic VO and the possible involvement of MMP-9 in myocardial contractile performance.

Ask AI

Helpful

Bookmark

View Full Paper