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

Author(s):Show less -

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]

Affiliation

^[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

• Document type: Journal article
• Source: Biochemical Pharmacology; v. 193, NOV 2021.
• Web of Science Citations: 0

Abstract

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)

• FAPESP's process: 17/03580-9 - Biochemical, structural and functional evaluation of a phosphodiesterase from Crotalus durissus collilineatus venom
• Grantee: Isadora Sousa de Oliveira
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 16/09345-9 - Intracellular proteolytic effects of calpain-1 and matrix metaloproteinase (MMP)-2 in hypertension-induced hypertrophic remodeling and heart failure
• Grantee: Michele Mazzaron de Castro
• Support Opportunities: Regular Research Grants
• FAPESP's process: 14/11412-0 - Intracellular effect of matrix metalloproteinase (MMP)-2 in hypertension-mediated cardiovascular dysfunction
• Grantee: Michele Mazzaron de Castro
• Support Opportunities: Regular Research Grants