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A Murine Closed-chest Model of Myocardial Ischemia and Reperfusion
Published on: July 17, 2012
Temporal exposure of cryptic collagen epitopes within ischemic muscle during hindlimb reperfusion
Paul J Gagne1, Nikita Tihonov, Xialou Li
1New York University School of Medicine, Department of Surgery, 530 First Avenue, Suite 6F, New York, NY 10016, USA. paul.gagne@med.nyu.edu
Abstract:
Chronic limb-threatening ischemia is a devastating disease with limited surgical options. However, inducing controlled angiogenesis and enhancing reperfusion holds therapeutic promise. To gain a better understanding of the mechanisms that contribute to limb reperfusion, we examined the temporal biochemical and structural changes occurring within the extracellular matrix of ischemic skeletal muscle. Both the latent and active forms of MMP-2 and -9 significantly increased during the active phase of limb reperfusion. Moreover, small but significant alterations in tissue inhibitors of metalloproteinase levels also occurred during a similar time course, consistent with a net increase in extracellular matrix remodeling. This temporal increase in MMP activity coincided with enhanced exposure of the unique HU177 cryptic collagen epitope. Although the HUIV26 cryptic collagen epitope has been implicated in angiogenesis, little is known concerning such epitopes within ischemic muscle tissue. Here, we provide the first evidence that a functionally distinct cryptic collagen epitope (HU177) is temporally exposed in ischemic muscle tissue during the active phase of reperfusion. Interestingly, the exposure of the HU177 epitope was greatly diminished in MMP-9 null mice, corresponding with significantly reduced limb reperfusion. Therefore, the regulated exposure of a unique cryptic collagen epitope within ischemic muscle suggests an important role for collagen remodeling during the active phase of ischemic limb reperfusion.
Insights
Matrix metalloproteinase (MMP) activity and a unique collagen epitope (HU177) increase during limb reperfusion. MMP-9 is crucial for HU177 exposure and effective reperfusion in ischemic muscle.
Area of Science:
- Biochemistry
- Vascular Biology
- Extracellular Matrix Biology
Background:
- Chronic limb-threatening ischemia presents limited therapeutic options.
- Controlled angiogenesis and enhanced reperfusion are promising treatment strategies.
- Understanding limb reperfusion mechanisms is critical for developing new therapies.
Purpose of the Study:
- To investigate the temporal biochemical and structural changes in the extracellular matrix of ischemic skeletal muscle during reperfusion.
- To elucidate the role of matrix metalloproteinases (MMPs) and cryptic collagen epitopes in this process.
Main Methods:
- Analysis of MMP-2 and MMP-9 activity and tissue inhibitors of metalloproteinase levels in ischemic muscle.
- Examination of the temporal exposure of cryptic collagen epitopes, specifically HU177.
- Comparison of reperfusion and HU177 epitope exposure in wild-type and MMP-9 null mice.
Main Results:
- Significant increases in both latent and active forms of MMP-2 and MMP-9 were observed during active limb reperfusion.
- Alterations in tissue inhibitors of metalloproteinase levels indicated increased extracellular matrix remodeling.
- A unique cryptic collagen epitope, HU177, was temporally exposed during reperfusion.
- HU177 epitope exposure was significantly reduced in MMP-9 null mice, correlating with diminished limb reperfusion.
Conclusions:
- Regulated exposure of the HU177 cryptic collagen epitope is a key event during the active phase of ischemic limb reperfusion.
- Matrix metalloproteinase-9 plays a critical role in the exposure of HU177 and subsequent limb reperfusion.
- These findings highlight the importance of collagen remodeling in therapeutic strategies for chronic limb-threatening ischemia.
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