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

Heart failure is a leading cause of hospitalization worldwide, and evaluating the severity of heart failure often relies on the ejection fraction. Matrix metalloproteinases (MMPs) are crucial for tissue remodeling, and their dysregulation is linked to various pathologies, including cardiovascular diseases. Prior studies have demonstrated that MMP-9 gene deletion can promote angiogenesis, attenuate inflammation, and prevent vascular leakiness. Although MMP-9 is known to contribute to heart failure, it remains unclear whether the lack of the MMP-9 gene impacts heart failure with reduced ejection fraction (HFrEF) by preserving EF. We investigated whether removing the MMP-9 gene can help maintain ejection fraction during the transition from diastolic to systolic heart failure. To test the hypothesis, surgical creation of an arteriovenous fistula (AVF) was made between the abdominal aorta and inferior vena cava ~ 0.5 cm below the left kidney of the mice using a 25-gauge needle to create a chronic volume overload, a "single-hit" model of HFrEF. The mice were grouped into four separate categories: (i) Wild type (WT) sham, (ii) WT-AVF, (iii) MMP9-KO-sham, and (iv) MMP9-KO-AVF. The "in-gel" zymography technique quantified proteolytic activity on substrate gels. Protein expression levels of heart tissues were assessed by the Western blots. The multi-organ injury was assessed using tissue-specific creatine kinase isoforms, and cardiac function-related datasets were collected using an ultrasound procedure and myobath. The results showed that MMP-9 gene ablation preserves ejection fraction during HFrEF by enhancing the processes of (a) cell synthesis, adhesion, and contraction signaling, (b) mitigating multi-organ injury, (c) mitigating mitophagy, and (d) mitigating endocardial endothelial myocyte uncoupling.