Sarcoplasmic reticulum calcium ATPase (SERCA) proteolysis by matrix metalloproteinase-2 contributes to vascular dysfunction in early hypertension

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de Mello, Marcela M. Blascke ; Neves, Viviano Gomes de Oliveira ; Parente, Juliana Montenegro ; Pernomian, Laena ; de Oliveira, Isadora Sousa ; Pedersoli, Carina Amarante ; Awata, Wanessa Mayumi Carvalho ; Tirapelli, Carlos Renato ; Arantes, Eliane Candiani ; Tostes, Rita de Cassia A. ; Schulz, Richard ; de Castro, Michele Mazzaron

• Tipo de documento: Artigo Científico
• Fonte: European Journal of Pharmacology; v. 983, p. 9-pg., 2024-09-07.

Resumo

Aims: Hypertension is associated with an increased activity of matrix metalloproteinase (MMP)-2 in the vasculature, which, in turn, proteolyzes extra- and intracellular proteins that lead to vascular dysfunction. The activity of sarcoplasmic reticulum calcium ATPase (SERCA) is decreased in the aortas of hypertensive rats. Increased activity of MMP-2 proteolyzed SERCA in rat heart during ischemia and reperfusion injury, thus impairing cardiac function. Therefore, we examined whether increased activity of MMP-2 in early hypertension contributes to proteolyze SERCA in the aortas, thus leading to maladaptive vascular remodeling and dysfunction. Main methods: Male Sprague-Dawley rats were submitted to two kidney-one clip (2K-1C) or Sham surgery and treated with doxycycline. Systolic blood pressure (SBP) was assessed by tail-cuff plethysmography. After 7 days, aortas were collected for zymography assays, Western blot to SERCA, ATPase activity assay, vascular reactivity, Ki-67 immunofluorescence and hematoxylin/eosin stain. Key findings: SBP was increased in 2K-1C rats and doxycycline did not reduce it, but decreased MMP-2 activity and prevented SERCA proteolysis in aortas. Cross sectional area, media to lumen ratio and Ki-67 were all increased in the aortas of hypertensive rats and doxycycline decreased Ki-67. In 2K-1C rats, arterial relaxation to acetylcholine was impaired and doxycycline ameliorated it. Significance: doxycycline reduced MMP-2 activity in aortas of 2K-1C rats and prevented proteolysis of SERCA and its dysfunction, thus ameliorating hypertension-induced vascular dysfunction. (AU)

• Processo FAPESP: 19/09174-8 - Ativação extra- e intracelular da metaloproteinase da matriz (MMP)-2 por estresse oxidativo e o remodelamento da hipertensão via mecanismos dependentes e independentes da matriz extracelular
• Beneficiário: Michele Mazzaron de Castro
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 21/11936-3 - Centro de Ciência Translacional e Desenvolvimento de Biofármacos
• Beneficiário: Benedito Barraviera
• Modalidade de apoio: Auxílio à Pesquisa - Centros de Ciência para o Desenvolvimento
• Processo FAPESP: 20/13176-3 - Descoberta de anticorpos monoclonais humanos (scFv) com reatividade cruzada e pH-dependentes para as metaloproteases de Bothrops spp
• Beneficiário: Isadora Sousa de Oliveira
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 20/02619-1 - Ação proteolítica da metaloproteinase de matriz (MMP)-2 sobre a cálcio ATPase do retículo sarcoplasmático (SERCA) e as alterações vasculares morfofuncionais da Hipertensão Arterial
• Beneficiário: Marcela Maria Blascke de Mello
• Modalidade de apoio: Bolsas no Brasil - Doutorado Direto
• Processo FAPESP: 22/04888-5 - Antioxidante e modulação imunológica nas fases gestacional e neonatal reduzem o remodelamento arterial hipertrófico e a Hipertensão na prole adulta de ratos hipertensos por diminuir fatores inflamatórios e a atividade da MMP-2
• Beneficiário: Michele Mazzaron de Castro
• Modalidade de apoio: Auxílio à Pesquisa - Regular