Systems Network Genomic Analysis Reveals Cardioprotective Effect of MURC/Cavin‐4 Deletion Against Ischemia/Reperfusion Injury

Abstract

BackgroundIschemia/reperfusion (I/R) injury is a critical issue in the development of treatment strategies for ischemic heart disease. MURC (muscle‐restricted coiled‐coil protein)/Cavin‐4 (caveolae‐associated protein 4), which is a component of caveolae, is involved in the pathophysiology of dilated cardiomyopathy and cardiac hypertrophy. However, the role of MURC in cardiac I/R injury remains unknown.Methods and ResultsThe systems network genomic analysis based on PC‐corr network inference on microarray data between wild‐type and MURC knockout mouse hearts predicted a network of discriminating genes associated with reactive oxygen species. To demonstrate the prediction, we analyzed I/R‐injured mouse hearts. MURC deletion decreased infarct size and preserved heart contraction with reactive oxygen species–related molecule EGR1 (early growth response protein 1) and DDIT4 (DNA‐damage‐inducible transcript 4) suppression in I/R‐injured hearts. Because PC‐corr network inference integrated with a protein–protein interaction network prediction also showed that MURC is involved in the apoptotic pathway, we confirmed the upregulation of STAT3 (signal transducer and activator of transcription 3) and BCL2 (B‐cell lymphoma 2) and the inactivation of caspase 3 in I/R‐injured hearts of MURC knockout mice compared with those of wild‐type mice. STAT3 inhibitor canceled the cardioprotective effect of MURC deletion in I/R‐injured hearts. In cardiomyocytes exposed to hydrogen peroxide, MURC overexpression promoted apoptosis and MURC knockdown inhibited apoptosis. STAT3 inhibitor canceled the antiapoptotic effect of MURC knockdown in cardiomyocytes.ConclusionsOur findings, obtained by prediction from systems network genomic analysis followed by experimental validation, suggested that MURC modulates cardiac I/R injury through the regulation of reactive oxygen species–induced cell death and STAT3‐meditated antiapoptosis. Functional inhibition of MURC may be effective in reducing cardiac I/R injury.

Dietary α-Linolenic Acid Counters Cardioprotective Dysfunction in Diabetic Mice: Unconventional PUFA Protection

“…Other data indicate n-3 PUFA intake suppresses vascular caveolin-1, albeit in a model of experimental menopause [ 62 ]. We find no evidence of ALA-dependent changes in the expression or sub-cellular localization of caveolins 1 and 3 in T2D hearts, or of cavin 1 or 4 expression, also critical to caveolar structure/function, cardiac stress-resistance and signaling [ 68 , 69 , 70 ]. Whether this reflects a limited capacity of dietary ALA to modify cardiac microdomains, compared with DHA or EPA for example, remains to be tested; there is evidence of differing membrane incorporation and cardiovascular influences of PUFA sub-types [ 3 , 27 , 28 , 95 , 96 ].…”

“…Caveolin-3 and cavin-1 are essential to the structural integrity and function of caveolae [114], and to myocardial I-R tolerance and cardioprotection [39,40,68]. Caveolin-1 may also be protective [67], whereas cavin-4 appears to limit cardiac stress-resistance [70]. Prior studies indicate ALA may augment caveolin-3 in cardiomyocytes and cardiomyopathic hearts [46], and counters both inflammation-dependent down-regulation of skeletal myoblast caveolin-3 [60] and up-regulation of endothelial caveolin-1 [115].…”

“…As discussed recently [ 44 ], this model is relevant to the pattern of T2D onset in humans, and avoids complications of adaptive cardioprotection evident in acute disease models, differing cardiac stress responses in early onset (e.g., genetic or disease-prone inbred models) vs. adult onset disease, and potential intrauterine programming of stress phenotype in genetic models. We focus on myocardial responses to I-R and IPC, while assessing basal expression of caveolins 1 and 3 (known to influence ischemic tolerance and IPC [ 39 , 40 , 67 ]) together with cavins 1 and 4: more recently identified determinants of caveolar structure/function and stress-resistance [ 68 , 69 , 70 ] whose sensitivities to dietary lipids are unknown.…”

Energy‐sparing by 2‐methyl‐2‐thiazoline protects heart from ischaemia/reperfusion injury

“…A mouse model of cardiac I/R injury was established as previously described, with slight modifications 23 . In 10 week‐old C57BL/6 background male mice, the left anterior descending coronary arteries were ligated under 1.0% isoflurane anaesthesia for 30 min before reperfusion.…”

MCP-1 mediates ischemia-reperfusion-induced cardiomyocyte apoptosis via MCPIP1 and CaSR

“…The left anterior descending coronary artery was then transiently ligated (or tied with a slipknot) using a 6-0 polypropylene suture for a 30-min ischemic period. After 30 min of ischemia, microsurgical scissors were used to cut the knot in the ligature (or the slipknot was released), and the heart was perfused for 2.5 h. Immediately after finishing the reperfusion time, the mice were euthanized, and the heart was excised for the next experiment (7,27). All animal procedures were performed in strict accordance with the Animal Research: Reporting of In Vivo Experiments guidelines, and the animal protocols were approved by the Institutional Animal Care and Use Committee of the Medical School of Southeast University.…”