Abstract P115: Troponin I and Dystrophin Proteolysis by Matrix Metalloproteinase 2 Contribute to Chronic Cardiac Remodeling and Dysfunction in Renovascular Hypertension

Cardiomyocyte dedifferentiation may be an important source of proliferating cardiomyocytes facilitating cardiac repair. Cardiomyocyte dedifferentiation and proliferation induced by oncostatin-M (OSM) is characterized by sarcomere degeneration. However, the mechanism underlying sarcomere degeneration remains unclear. We hypothesized that this process may involve matrix metalloproteinase-2 (MMP-2), a key protease localized at the sarcomere in cardiomyocytes. We tested the hypothesis that MMP-2 is involved in the sarcomere degeneration that characterizes cardiomyocyte dedifferentiation. Confocal immunofluorescence and biochemical methods were used to explore the role of MMP-2 in OSM-induced dedifferentiation of neonatal rat ventricular myocytes (NRVM). OSM caused a concentration- and time-dependent loss of sarcomeric α-actinin and troponin-I in NRVM. Upon OSM-treatment, the mature sarcomere transformed to a phenotype resembling a less-developed sarcomere, i.e., loss of sarcomeric proteins and Z-disk transformed into disconnected Z bodies, characteristic of immature myofibrils. OSM dose dependently increased MMP-2 activity. Both the pan-MMP inhibitor GM6001 and the selective MMP-2 inhibitor ARP 100 prevented sarcomere degeneration induced by OSM treatment. OSM also induced NRVM cell cycling and increased methyl-thiazolyl-tetrazolium (MTT) staining, preventable by MMP inhibition. These results suggest that MMP-2 mediates sarcomere degeneration in OSM-induced cardiomyocyte dedifferentiation and thus potentially contributes to cardiomyocyte regeneration.

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Matrix Metalloproteinase-2 Inhibition in Acute Ischemia-Reperfusion Heart Injury—Cardioprotective Properties of Carvedilol

Pharmaceuticals ◽

10.3390/ph14121276 ◽

2021 ◽

Vol 14 (12) ◽

pp. 1276

Author(s):

Monika Skrzypiec-Spring ◽

Joanna Urbaniak ◽

Agnieszka Sapa-Wojciechowska ◽

Jadwiga Pietkiewicz ◽

Alina Orda ◽

...

Keyword(s):

Matrix Metalloproteinase ◽

Troponin I ◽

Ischemia Reperfusion ◽

Matrix Metalloproteinase 2 ◽

Acute Ischemia ◽

Mechanical Function ◽

Cardiac Contractile ◽

Injury Group ◽

Rat Hearts ◽

Cardiac Contractile Dysfunction

Matrix metalloproteinase 2 (MMP-2) is activated in hearts upon ischemia-reperfusion (IR) injury and cleaves sarcomeric proteins. It was shown that carvedilol and nebivolol reduced the activity of different MMPs. Hence, we hypothesized that they could reduce MMPs activation in myocytes, and therefore, protect against cardiac contractile dysfunction related with IR injury. Isolated rat hearts were subjected to either control aerobic perfusion or IR injury: 25 min of aerobic perfusion, followed by 20 min global, no-flow ischemia, and reperfusion for 30 min. The effects of carvedilol, nebivolol, or metoprolol were evaluated in hearts subjected to IR injury. Cardiac mechanical function and MMP-2 activity in the heart homogenates and coronary effluent were assessed along with troponin I content in the former. Only carvedilol improved the recovery of mechanical function at the end of reperfusion compared to IR injury hearts. IR injury induced the activation and release of MMP-2 into the coronary effluent during reperfusion. MMP-2 activity in the coronary effluent increased in the IR injury group and this was prevented by carvedilol. Troponin I levels decreased by 73% in IR hearts and this was abolished by carvedilol. Conclusions: These data suggest that the cardioprotective effect of carvedilol in myocardial IR injury may be mediated by inhibiting MMP-2 activation.

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Ethanol extract from Epimedium brevicornum attenuates left ventricular dysfunction and cardiac remodeling through down-regulating matrix metalloproteinase-2 and -9 activity and myocardial apoptosis in rats with congestive heart failure

International Journal of Molecular Medicine ◽

10.3892/ijmm.21.1.117 ◽

2008 ◽

Cited By ~ 1

Author(s):

Yao-Hong Song ◽

Bao-Shi Li ◽

Xiang-Min Chen ◽

Hui Cai

Keyword(s):

Heart Failure ◽

Congestive Heart Failure ◽

Matrix Metalloproteinase ◽

Left Ventricular Dysfunction ◽

Cardiac Remodeling ◽

Ventricular Dysfunction ◽

Ethanol Extract ◽

Left Ventricular ◽

Matrix Metalloproteinase 2 ◽

Myocardial Apoptosis

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Intracellular Regulation of Matrix Metalloproteinase-2 Activity: New Strategies in Treatment and Protection of Heart Subjected to Oxidative Stress

Scientifica ◽

10.1155/2013/130451 ◽

2013 ◽

Vol 2013 ◽

pp. 1-12 ◽

Cited By ~ 18

Author(s):

Grzegorz Sawicki

Keyword(s):

Matrix Metalloproteinase ◽

Molecular Mechanisms ◽

Troponin I ◽

Contractile Function ◽

Ischemia Reperfusion ◽

Matrix Metalloproteinase 2 ◽

Acid Oxidation ◽

Intracellular Regulation ◽

Heart Injury ◽

New Strategies

Much is known regarding cardiac energy metabolism in ischemia/reperfusion (I/R) injury. Under aerobic conditions, the heart prefers to metabolize fatty acids, which contribute to 60–80% of the required ATP. During ischemia, anaerobic glycolysis increases and becomes an important source of ATP for preservation of ion gradients. With reperfusion, fatty acid oxidation quickly recovers and again predominates as the major source of mitochondrial oxidative metabolism. Although a number of molecular mechanisms have been implicated in the development of I/R injury, their relative contributions remain to be determined. One such mechanism involves the proteolytic degradation of contractile proteins, such as troponin I (TnI), myosin heavy chain, titin, and the myosin light chains (MLC1 and MLC2) by matrix metalloproteinase-2 (MMP-2). However, very little is known about intracellular regulation of MMP-2 activity under physiological and pathological conditions. Greater understanding of the mechanisms that govern MMP-2 activity may lead to the development of new therapeutic strategies aimed at preservation of the contractile function of the heart subjected to myocardial infarction (MI) or I/R. This review discusses the intracellular mechanisms controlling MMP-2 activity and highlights a new intracellular therapeutic direction for the prevention and treatment of heart injury.

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The Nuclear FactorkappaB Inhibitor Pyrrolidine Dithiocarbamate Prevents Cardiac Remodelling and Matrix Metalloproteinase-2 Up-Regulation in Renovascular Hypertension

Basic & Clinical Pharmacology & Toxicology ◽

10.1111/bcpt.12400 ◽

2015 ◽

pp. n/a-n/a ◽

Cited By ~ 3

Author(s):

Stefany B. A. Cau ◽

Danielle A. Guimaraes ◽

Elen Rizzi ◽

Carla S. Ceron ◽

Raquel F. Gerlach ◽

...

Keyword(s):

Matrix Metalloproteinase ◽

Renovascular Hypertension ◽

Cardiac Remodelling ◽

Matrix Metalloproteinase 2 ◽

Pyrrolidine Dithiocarbamate

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Abstract 810: Impact of Elevated Plasma Matrix Metalloproteinase-2 on Prognosis in Hypertrophic Cardiomyopathy: Evidence from Long-Term Follow-Up of Genotyped Patients

Circulation ◽

10.1161/circ.118.suppl_18.s_615-a ◽

2008 ◽

Vol 118 (suppl_18) ◽

Author(s):

Eiichi Masuta ◽

Hidekazu Ino ◽

Noboru Fujino ◽

Katsuharu Uchiyama ◽

Kenshi Hayashi ◽

...

Keyword(s):

Matrix Metalloproteinase ◽

Cardiac Troponin ◽

Troponin I ◽

Troponin T ◽

Left Ventricular ◽

Matrix Metalloproteinase 2 ◽

Cardiac Events ◽

Group A ◽

Group B

Background: Previous studies suggest that production of matrix metalloproteinase-2 (MMP-2) which is responsible for cardiac remodeling could determine prognosis of hypertrophic cardiomyopahty (HCM). However, few data exist regarding the importance of MMP-2 production in clinical settings. Therefore, we determined MMP-2 levels correlated to prognosis in HCM with sarcomere gene mutations. Methods and Results: Echocardiography and determination of plasma MMP-2 levels by enzyme-linked immunoassay were simultaneously performed in 31 HCM patients (22 women, mean age 56±12 years) with sarcomere protein gene mutation including 22 for cardiac troponin I, 5 for cardiac myosin binding-protein C, 3 for cardiac troponin T and 1 for beta-myosin heavy chain. Major cardiac events such as hospitalization due to congestive heart failure or ventricular fibrillation and mortality were prospectively examined for follow-up period of 48.4±29.1 months. When patients were divided into two groups (Group A: MMP-2 ≥800 ng/ml n=16 and Group B: MMP-2<800ng/ml n=15), there was no differences in mean age (59.4±11.7 year vs 53.1±11.3 year, p=0.13). On echocardiograms, interventricular septal thickness in group A (11.7±4.2 mm) was smaller than that in group B (15.9±4.8 mm, p<0.05) and percent fractional shortening (FS) was significantly impaired in group A (24.8±12.5%) in comparison with that in group B (37.7±8.1%, p=0.002). There was negative correlation between the MMP-2 levels and FS (p<0.001, r=0.76). The frequency of cardiac events was significantly higher in group A (10 patients of 16 patients) than in group B (1 patient of 15 patients, p=0.0012). Importantly, 5 patients of group A died, although none of groupB patients did (p=0.018). Conclusion: These results demonstrate that the high plasma concentration of MMP-2 (≥800 ng/ml) could be a predictor of prognosis in HCM with sarcomere mutations probably through reflecting impaired left ventricular function.

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