MMP inhibition attenuates hypertensive eccentric cardiac hypertrophy and dysfunction by preserving troponin I and dystrophin

Autor(es):Mostrar menos -

Parente, Juliana Montenegro ^[1] ; Mello, Marcela Maria Blascke de ^[1] ; Silva, Pedro Henrique Leite da ^[1] ; Omoto, Ana Carolina Mieko ^[2] ; Pernomian, Laena ^[1] ; Oliveira, Isadora Sousa de ^[3] ; Mahmud, Zabed ^[4] ; Fazan, Jr., Rubens ^[2] ; Arantes, Eliane Candiani ^[3] ; Schulz, Richard ^[5] ; Castro, Michele Mazzaron de ^[1]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Pharmacol, Av Bandeirantes 3900, BR-14049900 Ribeirao Preto, SP - Brazil

^[2] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Physiol, Av Bandeirantes 3900, BR-14049900 Ribeirao Preto, SP - Brazil

^[3] Univ Sao Paulo, Sch Pharmaceut Sci Ribeirao Preto, Dept Biomol Sci, Av Bandeirantes 3900, BR-14049900 Ribeirao Preto, SP - Brazil

^[4] Univ Alberta, Dept Biochem, 474 Med Sci Bldg, Edmonton, AB T6G 2R3 - Canada

^[5] Univ Alberta, Mazankowski Alberta Heart Inst, Dept Pediat & Pharmacol, 462 Heritage Med Res Ctr, Edmonton, AB T6G 2S2 - Canada

• Tipo de documento: Artigo Científico
• Fonte: Biochemical Pharmacology; v. 193, NOV 2021.
• Citações Web of Science: 0

Resumo

Purpose: Cardiac transition from concentric (C-LVH) to eccentric left ventricle hypertrophy (E-LVH) is a mal-adaptive response of hypertension. Matrix metalloproteinases (MMPs), in particular MMP-2, may contribute to tissue remodeling by proteolyzing extra-and intracellular proteins. Troponin I and dystrophin are two potential targets of MMP-2 examined in this study and their proteolysis would impair cardiac contractile function. We hypothesized that MMP-2 contributes to the decrease in troponin I and dystrophin in the hypertensive heart and thereby controls the transition from C-LVH to E-LVH and cardiac dysfunction. Methods: Male Wistar rats were divided into sham or two kidney-1 clip (2K-1C) hypertensive groups and treated with water (vehicle) or doxycycline (MMP inhibitor, 15 mg/kg/day) by gavage from the tenth to the sixteenth week post-surgery. Tail-cuff plethysmography, echocardiography, gelatin zymography, confocal microscopy, western blot, mass spectrometry, in silico protein analysis and immunofluorescence were performed. Results: 6 out of 23 2K-1C rats (26%) had E-LVH followed by reduced ejection fraction. The remaining had C-LVH with preserved cardiac function. Doxycycline prevented the transition from C-LVH to E-LVH. MMP activity is increased in C-LVH and E-LVH hearts which was inhibited by doxycycline. This effect was associated with an increase in troponin I cleavage products and a decline in dystrophin in the left ventricle of E-LVH rats, which was prevented by doxycycline. Conclusion: Hypertension causes increased cardiac MMP-2 activity which proteolyzes troponin I and dystrophin, contributing to the transition from C-LVH to E-LVH and cardiac dysfunction. (AU)

• Processo FAPESP: 17/03580-9 - Avaliação bioquímica, estrutural e funcional de uma fosfodiesterase da peçonha de Crotalus durissus collilineatus
• Beneficiário: Isadora Sousa de Oliveira
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 16/09345-9 - Contribuição proteolítica intracelular da calpaína-1 e metaloproteinase da matriz (MMP)-2 no remodelamento hipertrófico e insuficiência cardíaca da hipertensão arterial
• Beneficiário: Michele Mazzaron de Castro
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 14/11412-0 - Ações proteolíticas intracelulares da metaloproteinase de matriz (MMP-2) nas alterações cardiovasculares da hipertensão arterial
• Beneficiário: Michele Mazzaron de Castro
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 04/08868-0 - Consolidação do Centro de Microscopia Funcional do Campus da USP/ Ribeirão Preto
• Beneficiário: Roy Edward Larson
• Modalidade de apoio: Auxílio à Pesquisa - Programa Equipamentos Multiusuários