MMP-9 Gene Ablation Preserves Ejection Fraction During "Single-Hit" Model of HFrEF

Area of Science:

• Cardiovascular Biology
• Molecular Cardiology
• Pathophysiology of Heart Failure

Background:

• Heart failure with reduced ejection fraction (HFrEF) is a major cause of hospitalization globally.
• Matrix metalloproteinases (MMPs), particularly MMP-9, are implicated in cardiovascular diseases and tissue remodeling.
• The specific role of MMP-9 in preserving ejection fraction during HFrEF progression remains unclear.

Purpose of the Study:

• To investigate the impact of MMP-9 gene deletion on maintaining ejection fraction (EF) in a mouse model of HFrEF.
• To determine if MMP-9 deficiency can prevent the transition from diastolic to systolic heart failure.
• To elucidate the mechanisms by which MMP-9 influences cardiac function and organ integrity in HFrEF.

Main Methods:

• A chronic volume overload HFrEF model was created in mice using an arteriovenous fistula (AVF) between the aorta and inferior vena cava.
• Mice were grouped into wild type (WT) sham, WT-AVF, MMP9-knockout (KO)-sham, and MMP9-KO-AVF.
• Cardiac function was assessed via ultrasound and myobath; proteolytic activity by zymography; protein expression by Western blot; and multi-organ injury by creatine kinase isoforms.

Main Results:

• MMP-9 gene ablation significantly preserved ejection fraction in the HFrEF model.
• MMP-9 deficiency mitigated multi-organ injury and endocardial endothelial myocyte uncoupling.
• Enhanced cell synthesis, adhesion, and contraction signaling pathways were observed in MMP-9 deficient hearts.
• Mitophagy was reduced in MMP-9 knockout mice, suggesting a protective effect.

Conclusions:

• MMP-9 gene deletion preserves ejection fraction in HFrEF.
• MMP-9 ablation confers protection against multi-organ damage and cardiac dysfunction.
• Targeting MMP-9 may represent a novel therapeutic strategy for managing heart failure with reduced ejection fraction.