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Intracellular proteolytic effects of calpain-1 and matrix metaloproteinase (MMP)-2 in hypertension-induced hypertrophic remodeling and heart failure


Arterial hypertension significantly leads to hypertrophic cardiac remodeling and dysfunction that usually proceed to heart failure. Increased activity of calpain and matrix metalloproteinase (MMP)-2 may contribute to hypertension-induced cardiac hypertrophy and systolic-diastolic dysfunction. Chronic treatment with subantimocrobial dosage of the MMP inhibitor, doxycycline, or calpastatin, an endogenous inhibitor of calpain, decreases hypertension-induced increased MMP-2 and calpain-1 activities, hypertrophic remodeling and cardiac dysfunction. By using the two kidney-one clip (2K-1C) model of hypertension, we observed that the transition from hypertrophic to eccentric cardiac remodeling occurs at 16 weeks of hypertension, and it was accompanied by a significant increase in MMP-2 activity. Both calpain-1 and MMP-2 proteolyze many identical intracellular targets into cardiomyocytes, e.g. troponin I and dystrophin, thus resulting in cardiac dysfunction during ischemia and reperfusion injury. Therefore, instead to investigate only one intracellular proteolytic system, it would be interesting to analyze whether there is a linkage or synergism between the proteolytic effects of calpain-1 and MMP-2 in hypertension-induced chronic cardiac remodeling and heart failure. To establish this, the 2K-1C hypertension model and treatment with doxycycline and/or verapamil will be used. Troponin I and calponin-1 will be examined in the project as potential targets to be degraded by MMP-2 and/or calpain-1 in the cardiomyocytes during hypertension, since they mainly regulate the cardiac contractile apparatus. The results from this project will assist in the understanding of how the cardiac contractile apparatus is regulated during hypertension. (AU)

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(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
PARENTE, JULIANA MONTENEGRO; MELLO, MARCELA MARIA BLASCKE DE; SILVA, PEDRO HENRIQUE LEITE DA; OMOTO, ANA CAROLINA MIEKO; PERNOMIAN, LAENA; OLIVEIRA, ISADORA SOUSA DE; MAHMUD, ZABED; FAZAN, JR., RUBENS; ARANTES, ELIANE CANDIANI; SCHULZ, RICHARD; et al. MMP inhibition attenuates hypertensive eccentric cardiac hypertrophy and dysfunction by preserving troponin I and dystrophin. Biochemical Pharmacology, v. 193, . (17/03580-9, 16/09345-9, 14/11412-0)

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