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- Title
Junctophilin-2 is a target of matrix metalloproteinase-2 in myocardial ischemia–reperfusion injury.
- Authors
Chan, Brandon Y. H.; Roczkowsky, Andrej; Cho, Woo Jung; Poirier, Mathieu; Lee, Tim Y. T.; Mahmud, Zabed; Schulz, Richard
- Abstract
Junctophilin-2 is a structural membrane protein that tethers T-tubules to the sarcoplasmic reticulum to allow for coordinated calcium-induced calcium release in cardiomyocytes. Defective excitation–contraction coupling in myocardial ischemia–reperfusion (IR) injury is associated with junctophilin-2 proteolysis. However, it remains unclear whether preventing junctophilin-2 proteolysis improves the recovery of cardiac contractile dysfunction in IR injury. Matrix metalloproteinase-2 (MMP-2) is a zinc and calcium-dependent protease that is activated by oxidative stress in myocardial IR injury and cleaves both intracellular and extracellular substrates. To determine whether junctophilin-2 is targeted by MMP-2, isolated rat hearts were perfused in working mode aerobically or subjected to IR injury with the selective MMP inhibitor ARP-100. IR injury impaired the recovery of cardiac contractile function which was associated with increased degradation of junctophilin-2 and damaged cardiac dyads. In IR hearts, ARP-100 improved the recovery of cardiac contractile function, attenuated junctophilin-2 proteolysis, and prevented ultrastructural damage to the dyad. MMP-2 was co-localized with junctophilin-2 in aerobic and IR hearts by immunoprecipitation and immunohistochemistry. In situ zymography showed that MMP activity was localized to the Z-disc and sarcomere in aerobic hearts and accumulated at sites where the striated JPH-2 staining was disrupted in IR hearts. In vitro proteolysis assays determined that junctophilin-2 is susceptible to proteolysis by MMP-2 and in silico analysis predicted multiple MMP-2 cleavage sites between the membrane occupation and recognition nexus repeats and within the divergent region of junctophilin-2. Degradation of junctophilin-2 by MMP-2 is an early consequence of myocardial IR injury which may initiate a cascade of sequelae leading to impaired contractile function.
- Subjects
SARCOPLASMIC reticulum; CYTOSKELETAL proteins; MEMBRANE proteins; WOUNDS &; injuries; OXIDATIVE stress
- Publication
Basic Research in Cardiology, 2019, Vol 114, Issue 6, pN.PAG
- ISSN
0300-8428
- Publication type
Article
- DOI
10.1007/s00395-019-0749-7