MMP-2: is too low as bad as too high in the cardiovascular system?

Hardy, Eugenio; Hardy-Sosa, Anette; Fernandez-Patron, Carlos

Hardy, Eugenio; Hardy-Sosa, Anette; Fernandez-Patron, Carlos.

Afiliação

Hardy E; Biotechnology Laboratory, Study Center for Research and Biological Evaluations, Institute of Pharmacy and Foods, University of Havana , Havana , Cuba.
Hardy-Sosa A; Faculty of Biology, University of Havana , Havana , Cuba.
Fernandez-Patron C; Department of Biochemistry, Cardiovascular Research Centre, Mazankowski Alberta Heart Institute, Faculty of Medicine and Dentistry, University of Alberta , Edmonton, Alberta , Canada.

Am J Physiol Heart Circ Physiol ; 315(5): H1332-H1340, 2018 11 01.

Article em En | MEDLINE | ID: mdl-30118342

RESUMO

Matrix metalloproteinase (MMP)-2 cleaves a broad spectrum of substrates, including extracellular matrix components (responsible for normal tissue remodeling) and cytokines (modulators of the inflammatory response to physiological insults such as tissue damage). MMP-2 expression is elevated in many cardiovascular pathologies (e.g., myocardial infarction, hypertensive heart disease) where tissue remodeling and inflammatory responses are perturbed. Thus, it has generally been assumed that blockade of MMP-2 activity will yield therapeutic effects. Here, we provide a counterargument to this dogma based on 1) preclinical studies on Mmp2-null ( Mmp2-/-) mice and 2) clinical studies on patients with inactivating MMP2 gene mutations. Furthermore, we put forward the hypothesis that, when MMP-2 activity falls below baseline, the bioavailability of proinflammatory cytokines normally cleaved and inactivated by MMP-2 increases, leading to the production of cytokines and cardiac secretion of phospholipase A2 activity into the circulation, which stimulate systemic inflammation that perturbs lipid metabolism in target organs. Finally, we suggest that insufficient understanding of the consequences of MMP-2 deficiency remains a major factor in the failure of MMP-2 inhibitor-based therapeutic approaches. This paucity of knowledge precludes our ability to effectively intervene in cardiovascular and noncardiovascular pathologies at the level of MMP-2.

Assuntos

Doenças Cardiovasculares/enzimologia; Sistema Cardiovascular/enzimologia; Metaloproteinase 2 da Matriz/metabolismo; Animais; Doenças Cardiovasculares/tratamento farmacológico; Doenças Cardiovasculares/genética; Doenças Cardiovasculares/fisiopatologia; Sistema Cardiovascular/efeitos dos fármacos; Sistema Cardiovascular/fisiopatologia; Citocinas/metabolismo; Modelos Animais de Doenças; Regulação Enzimológica da Expressão Gênica; Humanos; Mediadores da Inflamação/metabolismo; Metabolismo dos Lipídeos; Metaloproteinase 2 da Matriz/deficiência; Metaloproteinase 2 da Matriz/genética; Inibidores de Metaloproteinases de Matriz/uso terapêutico; Camundongos Knockout; Mutação; Fosfolipases A2/metabolismo; Transdução de Sinais; Especificidade por Substrato

Palavras-chave

heart; inflammation; matrix metalloproteinase; metabolism

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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Doenças Cardiovasculares / Sistema Cardiovascular / Metaloproteinase 2 da Matriz Tipo de estudo: Prognostic_studies Limite: Animals / Humans Idioma: En Revista: Am J Physiol Heart Circ Physiol Assunto da revista: CARDIOLOGIA / FISIOLOGIA Ano de publicação: 2018 Tipo de documento: Article País de afiliação: Cuba País de publicação: Estados Unidos

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