Related Experiment Video
Updated: Aug 14, 2026
Chronic Ovine Model of Right Ventricular Failure and Functional Tricuspid Regurgitation
Published on: March 17, 2023
Roles of MMP-2/-9 in cardiac dysfunction during early multiple organ failure in an ovine animal model
Jeremias Wohlschlaeger1, Henning D Stubbe, Klaus J Schmitz
1Institute of Pathology, University of Essen, Hufelandstr. 55, 45122 Essen, Germany.
Abstract:
Biventricular dilation and severe cardiac dysfunction are observed during septic shock. However, when endotoxemia and vasoconstrictor-masked hypovolemia work in concert in the pathogenesis of shock, the clinical scenario is more adverse compared to one of the insults acting alone. Matrix metalloproteinases (MMPs) are involved in chronic and acute heart failure by degrading the mechanical scaffold of the heart and several intracellular proteins. Therefore, the roles of MMP-2, MMP-9, MT1-MMP, focal adhesion kinase (FAK), and Paxillin in hearts of early multiple organ failure induced by norfenefrine-masked hypovolemia and endotoxemia were investigated in an ovine model. Experimental groups included (1) norfenefrine-masked hypovolemia plus endotoxemia (NMH+ENDO) (n=6), (2) norfenefrine-masked hypovolemia without endotoxemia (NMH) (n=6), (3) recurrent endotoxemia during normovolemia (ENDO) (n=6), and (4) healthy untreated controls (CON) (n=3). Apoptosis was determined by TUNEL-staining. Gel zymography revealed significantly increased MMP-2 activity in NMH+ENDO compared to ENDO and controls. MMP-9 activity was significantly elevated in all experimental groups. MMP-2 was significantly increased at the protein level, while MMP-9 was unaltered. MT1-MMP was not significantly changed in any group. Increased MMP activities were associated with cardiac deterioration. MMP-2/-9 activity and phosphorylated Paxillin (p-Paxillin) expression correlated positively with cardiomyocyte apoptosis. This study underscores the pivotal roles of MMP in acute cardiac dysfunction during early multiple organ failure in combined vasoconstrictor-masked hypovolemic and endotoxemia shock.
Insights
Matrix metalloproteinases (MMPs) contribute to cardiac dysfunction during combined endotoxemia and hypovolemic shock. Increased MMP-2 and MMP-9 activity correlates with heart damage and cardiomyocyte apoptosis in this severe condition.
Area of Science:
- Cardiovascular Physiology
- Pathophysiology of Shock
- Molecular Cardiology
Background:
- Septic shock can cause biventricular dilation and cardiac dysfunction.
- Combined endotoxemia and vasoconstrictor-masked hypovolemia worsen shock outcomes.
- Matrix metalloproteinases (MMPs) are implicated in heart failure by degrading cardiac structural proteins.
Purpose of the Study:
- Investigate the roles of MMP-2, MMP-9, MT1-MMP, focal adhesion kinase (FAK), and Paxillin in early multiple organ failure.
- Examine the impact of combined norfenefrine-masked hypovolemia and endotoxemia on cardiac MMPs and related proteins.
- Assess the correlation between MMP activity, cardiac dysfunction, and cardiomyocyte apoptosis.
Main Methods:
- Ovine model with experimental groups: combined insult (NMH+ENDO), hypovolemia only (NMH), endotoxemia only (ENDO), and controls (CON).
- Gel zymography to measure MMP-2 and MMP-9 activity.
- Western blotting for protein levels of MMPs, MT1-MMP, FAK, and Paxillin (including phosphorylated forms).
- TUNEL staining to quantify cardiomyocyte apoptosis.
Main Results:
- MMP-2 activity was significantly higher in the combined insult group (NMH+ENDO) compared to endotoxemia alone (ENDO) and controls (CON).
- MMP-9 activity was elevated across all experimental groups.
- Increased MMP-2 protein levels were observed, while MMP-9 protein remained unchanged. MT1-MMP showed no significant changes.
- Elevated MMP activities, particularly MMP-2 and MMP-9, correlated with cardiac deterioration and increased cardiomyocyte apoptosis, alongside elevated phosphorylated Paxillin.
Conclusions:
- Matrix metalloproteinases, especially MMP-2, play a critical role in acute cardiac dysfunction during combined vasoconstrictor-masked hypovolemic and endotoxemic shock.
- The study highlights the detrimental impact of combined insults on cardiac integrity.
- MMP activity and associated signaling pathways contribute to cardiomyocyte apoptosis and overall cardiac failure in this complex shock model.
