MMP-2 Inhibition Ameliorates Hypertension-Induced Eccentric Cardiac Hypertrophy and Failure by Preserving Troponin I and Dystrophin

MMP-2 Inhibition Ameliorates Hypertension-Induced Eccentric Cardiac Hypertrophy and Failure by Preserving Troponin I and Dystrophin

• Autor
• Juliana Montenegro Parente
• Co-autores
• Marcela Maria Blascke de Mello , Pedro Henrique Leite da Silva , Ana Carolina Mieko Omoto , Laena Pernomian , Isadora Sousa de Oliveira , Zabed Mahmud , Rubens Fazan Jr , Eliane Candiani Arantes Braga , Richard Schulz , Michele Mazzaron de Castro
• Resumo

• Introduction: We hypothesized that MMP-2 contributes to proteolyze troponin I and dystrophin levels in the hypertensive heart thus favoring the transition from concentric (C-LVH) to eccentric hypertrophy (E-LVH) and cardiac dysfunction. Methods: Male 7-week old Wistar rats (180-200g) were sham or two kidney-one clip (2K1C) operated and treated with water or doxycycline (MMP inhibitor, 15 mg/kg/day) by gavage from the tenth to the sixteenth week post-surgery. To establish this aim, echocardiogram, gel and in situ zymography, troponin I western blotting and mass spectrometry, and dystrophin in silico analysis and immunofluorescence were performed. Results were analyzed by two-way ANOVA or unpaired t test (Ethics Committee approval number: 023/2015-1). Results: About 25% of 2K1C (6 of 24) rats had E-LVH followed by reduced ejection fraction (n=6-17; 39.8 ± 2.9 vs. 66.2 ±1.6 and 63.1 ± 3.1, p<0.05). The remaining had C-LVH with preserved cardiac function (p>0.05). Doxycycline prevented the transition from C-LVH to E-LVH. MMP-2 activity increased in C-LVH (n= 5-9; 7.2 ± 0.5 vs. 5.6 ± 0.2 and 5.4 ± 0.3, p<0.05) and E-LVH hearts (n=6-13; 0.13 ± 0.02 vs. 0.09 ± 0.01 and 0.09 ± 0.01, p<0.05) and doxycycline inhibited it (n= 5-9; 5.5 ± 0.3, p<0.05). This was associated with an increase in troponin I cleavage products in E-LVH when compared to C-LVH (n= 4-11; 3.6e-008 ± 7.9e-009 vs. 2.0e-008 ± 2.3e-009, p<0.05) confirmed by western blotting and mass spectrometry. Moreover, about ten putative MMP-2 cleavage sites in rat dystrophin were found and, in fact, a decline in dystrophin levels was observed in E-LVH (n=5-9; 9.5 ± 2.1 vs. 15.6 ±1.7 and 15.7 ±1.4, p<0.05) which was prevented by doxycycline (16.9 ± 0.6, p<0.05). Conclusion: Hypertension causes increased cardiac MMP-2 activity which reduces both troponin I and dystrophin levels and contributes to the transition from C-LVH to E-LVH.

• Palavras-chave
• Matrix metalloproteinase-2; troponin I; dystrophin
• Modalidade
• Pôster
• Área Temática
• Sinalização celular