microRNA-17-5p downregulation inhibits autophagy and myocardial remodelling after myocardial infarction by targeting STAT3

Background: Calpain is up-regulated and implicated in cardiomyocyte apoptosis and myocardial remodelling post myocardial infarction. Endoplasmic reticulum (ER) stress is induced and contributes to myocardial injury in a variety of cardiac diseases. This study was to investigate whether calpain plays a role in ER stress, thereby mediating apoptosis in cardiomyocytes and myocardial remodelling after infarction. Methods and Results: In rat cardiomyoblasts H9C2 cells, over-expression of calpain-1 increased the protein levels of Bip and CHOP, indicative of ER stress, and induced apoptosis determined by a decrease in Bcl-2 and increases in caspase-3 activation and DNA fragmentation. Inhibition of calpain activity or ER stress prevented apoptosis induced by calpain-1 over-expression. In contrast, over-expression of calpain-2 failed to induce apoptosis. The induction of ER stress by calpain-1 might be mediated through SERCA2a/Calcium signaling as up-regulation of calpain-1 reduced SERCA2a protein and elevated intracellular free Calcium in H9C2 cells. In a mouse model of myocardial infarction induced by coronary artery ligation, calpain activity was increased and ER stress was induced in the infracted heart. Up-regulation of calpastatin, the endogenous calpain inhibitor, inhibited calpain activation, prevented ER stress and apoptosis, reduced myocardial remodelling and improved myocardial function after infarction in calpastatin transgenic mice compared with their wild-type littermates. Conclusion: Calpain-1 induces ER stress through the proteolysis of SERCA2a, thereby mediating apoptosis in cardiomyocytes. Inhibition of calpain prevents ER stress and apoptosis, reduces myocardial remodelling and dysfunction after infarction. Thus, ER stress may represent a novel mechanism by which calpain mediates myocardial injury in the infracted heart.

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Abstract P274: Cardiac-Specific Knockout of Capn4 Attenuates Myocardial Remodeling and Improves Function After Myocardial Infarction in Mice

Circulation Research ◽

10.1161/res.109.suppl_1.ap274 ◽

2011 ◽

Vol 109 (suppl_1) ◽

Author(s):

Jian Ma ◽

Meng Wei ◽

Hao Wang ◽

Weihua Liu ◽

Wei Zhu ◽

...

Keyword(s):

Myocardial Infarction ◽

Mouse Model ◽

Coronary Artery Ligation ◽

Down Regulation ◽

Artery Ligation ◽

Cardiac Apoptosis ◽

Myocardial Remodelling ◽

Calpain 2 ◽

Specific Deletion

Background - Calpain has been implicated in myocardial injury after myocardial infarction (MI). However, no direct evidence is available on the role of calpain in post-MI myocardial remodelling and dysfunction. The present study investigated the effects of cardiomyocyte-specific deletion of Capn4 , essential for calpain-1 and calpain-2 activities on myocardial remodelling and dysfunction following MI. Methods and Results - A novel mouse model with cardiomyocyte-specific deletion of Capn4 ( Capn4-ko ) was generated. MI was induced by left coronary artery ligation. Deficiency of Capn4 significantly reduced the protein levels and activities of calpain-1 and calpain-2 in the Capn4-ko heart. In vivo cardiac function was relatively improved in Capn4-ko mice at 7 and 30 days after MI compared with their wild-type littermates. Deletion of Capn4 reduced cardiac apoptosis, limited infarct expansion and infarct zone thinning, and prevented left ventricle dilation in Capn4-ko mice. Furthermore, myocardial collagen deposition and cardiomyocyte cross-sectional areas were significantly attenuated in Capn4-ko mice, which were accompanied by down-regulation of pro-fibrotic genes and hypertrophic genes. These effects of Capn4 knockout correlated with down-regulation of inflammatory mediators and normalization of matrix metalloproteinase (MMP)-9 activity in the non-infarct area of Capn4-ko mice after MI. In vivo mouse model of endotoxemia confirmed that calpain activation resulted in inflammatory gene expression and MMP-9 activity in the heart. Conclusions - Cardiomyocyte-specific knockout of calpain attenuates myocardial adverse remodelling and improves myocardial function after MI. These beneficial effects of calpain disruption may result from inhibition of cardiac apoptosis, inflammation and MMP-9 activity.

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CARDIAC-SPECIFIC KNOCKOUT OF CAPN4 ATTENUATES MYOCARDIAL REMODELLING AND IMPROVES FUNCTION AFTER MYOCARDIAL INFARCTION IN MICE

Heart ◽

10.1136/heartjnl-2012-302920a.140 ◽

2012 ◽

Vol 98 (Suppl 2) ◽

pp. E57.1-E57

Author(s):

Jian Ma ◽

Tianqing Peng

Keyword(s):

Myocardial Infarction ◽

Myocardial Remodelling

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An electron microscopic study of the intra-myocardial lesions in cases of acute myocardial infarction

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s042482010008328x ◽

1978 ◽

Vol 36 (2) ◽

pp. 484-485

Author(s):

Masahiro Ono ◽

Kaoru Aihara ◽

Gompachi Yajima

Keyword(s):

Myocardial Infarction ◽

Acute Myocardial Infarction ◽

Coronary Vessels ◽

Vascular Wall ◽

Vascular Changes ◽

Electron Microscopic ◽

Main Trunk ◽

Mechanical Destruction ◽

Transmission Electron ◽

Myocardial Lesions

The pathogenesis of the arteriosclerosis in the acute myocardial infarction is the matter of the extensive survey with the transmission electron microscopy in experimental and clinical materials. In the previous communication,the authors have clarified that the two types of the coronary vascular changes could exist. The first category is the case in which we had failed to observe no occlusive changes of the coronary vessels which eventually form the myocardial infarction. The next category is the case in which occlusive -thrombotic changes are observed in which the myocardial infarction will be taken placed as the final event. The authors incline to designate the former category as the non-occlusive-non thrombotic lesions. The most important findings in both cases are the “mechanical destruction of the vascular wall and imbibition of the serous component” which are most frequently observed at the proximal portion of the coronary main trunk.

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