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Published on: June 3, 2018
Transgenic MMP-2 expression induces latent cardiac mitochondrial dysfunction
Hui-Zhong Zhou1, Xiaokui Ma, Mary O Gray
1Cardiology Section, Department of Medicine, UCSF, VA Medical Center, 4150 Clement Street, 111C-5, San Francisco, CA 94121, USA.
Abstract:
Matrix metalloproteinases (MMPs) are central to the development and progression of dysfunctional ventricular remodeling after tissue injury. We studied 6 month old heterozygous mice with cardiac-specific transgenic expression of active MMP-2 (MMP-2 Tg). MMP-2 Tg hearts showed no substantial gross alteration of cardiac phenotype compared to age-matched wild-type littermates. However, buffer perfused MMP-2 Tg hearts subjected to 30 min of global ischemia followed by 30 min of reperfusion had a larger infarct size and greater depression in contractile performance compared to wild-type hearts. Importantly, cardioprotection mediated by ischemic preconditioning (IPC) was completely abolished in MMP-2 Tg hearts, as shown by abnormalities in mitochondrial ultrastructure and impaired respiration, increased lipid peroxidation, cell necrosis and persistently reduced recovery of contractile performance during post-ischemic reperfusion. We conclude that MMP-2 functions not only as a proteolytic enzyme but also as a previously unrecognized active negative regulator of mitochondrial function during superimposed oxidative stress.
Insights
Matrix metalloproteinases-2 (MMP-2) actively harms mitochondrial function during oxidative stress, abolishing cardioprotection. This finding reveals MMP-2 as a negative regulator, impacting heart injury recovery.
Area of Science:
- Cardiovascular Biology
- Mitochondrial Physiology
- Protease Function
Background:
- Matrix metalloproteinases (MMPs) are implicated in cardiac remodeling post-injury.
- Dysfunctional ventricular remodeling contributes to heart failure progression.
Purpose of the Study:
- To investigate the role of active matrix metalloproteinase-2 (MMP-2) in cardiac function and response to ischemia-reperfusion injury.
- To determine if MMP-2 affects cardioprotection mediated by ischemic preconditioning (IPC).
Main Methods:
- Utilized cardiac-specific transgenic mice expressing active MMP-2 (MMP-2 Tg).
- Assessed cardiac phenotype, infarct size, and contractile performance after global ischemia-reperfusion.
- Evaluated mitochondrial ultrastructure, respiration, lipid peroxidation, and cell necrosis in response to IPC.
Main Results:
- MMP-2 Tg hearts exhibited larger infarct sizes and impaired contractile function post-ischemia-reperfusion compared to wild-type.
- Ischemic preconditioning (IPC) failed to provide cardioprotection in MMP-2 Tg hearts.
- MMP-2 Tg hearts showed mitochondrial ultrastructural abnormalities, impaired respiration, increased lipid peroxidation, and cell necrosis.
Conclusions:
- Active MMP-2 acts as a negative regulator of mitochondrial function during oxidative stress.
- MMP-2 abolishes the protective effects of ischemic preconditioning.
- Elevated MMP-2 activity exacerbates cardiac injury and impairs recovery after ischemic events.
