Potential Sarcoplasmic Reticulum Calcium ATPase (SERCA) Proteolysis by Matrix Metalloproteinase (MMP)-2 May Contribute to Hypercontractility and Vascular Remodeling During Arterial Hypertension

Potential Sarcoplasmic Reticulum Calcium ATPase (SERCA) Proteolysis by Matrix Metalloproteinase (MMP)-2 May Contribute to Hypercontractility and Vascular Remodeling During Arterial Hypertension

• Autor
• Marcela Maria Blascke de Mllo
• Co-autores
• Juliana Montenegro Parente , Laena Pernomian , Pedro Henrique Leite Silva , Richard Schulz , Michele Mazzaron de Castro
• Resumo

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  Introduction: Matrix metalloproteinase (MMP)-2 proteolyzes extra- and intracellular proteins and contributes to arterial remodeling. Sarcoplasmic reticulum calcium ATPase (SERCA) controls cytosolic calcium concentrations ([Ca2+]i), thus maintaining vascular tone. Increased [Ca2+]i may enhance vasoconstriction in hypertension and activate nuclear factor of activated T-cells, thus leading to vascular smooth muscle cells (VSMC)s migration and proliferation. Knowing that the protein levels and activity of SERCA are reduced in hypertension and MMP-2 proteolyzes SERCA during myocardial ischemia and reperfusion, the hypothesis is that increased intracellular MMP-2 activity in hypertensive aortas contributes to decrease SERCA levels and activity, thus resulting in arterial remodeling and vascular hypercontractility. Methods: Male Sprague-Dawley rats were submitted to two kidneys-one clip (2K-1C) or sham surgery and were treated with doxycycline (doxy; 30 mg/kg/day) or water by gavage from third to seventh day post-surgery. Systolic blood pressure (SBP) was daily assessed by tail-cuff plethysmography and in the eighth day post-surgery, aortas were collected for gelatin and in situ zymography, western blot to SERCA and immunofluorescence to calcium. Statistical analysis was done by two-way ANOVA followed by Tukey post-test. The Ethics Committee in Animal Research of Ribeirao Preto Medical School approved all protocols (122/2019). Results: SBP increased in the 2K1C rats (160.363±2.980 vs 119.945±2.454 and 119.888±1.727; p<0.05; n=5-9) and was unaltered by doxy (153.884±2.923 vs 160.363±2.980; n=5-9). However, doxy significantly reduced (18.13±0.6889 vs 23.47±1.070; p<0.05; n=5-8) hypertension-induced increase in MMP-2 activity (23.47±1.070 vs 16.86±1.282 and 18.41±0.7225; p<0.05; n=5-8) and ameliorated the increased (1.415±0.4183 vs 0.2556±0.06911 and 0.2321±0.09224; p<0.05; n=4-8) proteolysis of SERCA. Besides, intracellular calcium levels were increased in 2K-1C group (18.67±1.629 vs 14.09±0.4482 and 11.89±1.244; p=0.08; n=3) and treatment with doxy reverted it (11.86±0.9434 vs 18.67±1.629; p<0.05; n=3). Conclusions: MMP-2 may contribute to SERCA proteolysis in aortas of hypertensive rats, which may contribute to the vascular alterations in hypertension.

• Palavras-chave
• Arterial hypertension, MMP-2, SERCA
• Modalidade
• Pôster
• Área Temática
• Sinalização celular