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[PMID]: | 28899987 |
[Au] Autor: | Li Y; Zhu G; Paolocci N; Zhang P; Takahashi C; Okumus N; Heravi A; Keceli G; Ramirez-Correa G; Kass DA; Murphy AM |
[Ad] Endereço: | From the Division of Cardiology, Department of Pediatrics (Y.L., N.O., A.H., G.R.-C., A.M.M.), Division of Cardiology, Department of Medicine (G.Z., N.P., C.T., G.K., D.A.K.), Department of Pharmacology and Molecular Sciences, Department of Biomedical Engineering (D.A.K.), and Deparment of Ophthalmo |
[Ti] Título: | Heart Failure-Related Hyperphosphorylation in the Cardiac Troponin I C Terminus Has Divergent Effects on Cardiac Function In Vivo. |
[So] Source: | Circ Heart Fail;10(9), 2017 Sep. | [Is] ISSN: | 1941-3297 |
[Cp] País de publicação: | United States |
[La] Idioma: | eng |
[Ab] Resumo: | BACKGROUND: In human heart failure, Ser199 (equivalent to Ser200 in mouse) of cTnI (cardiac troponin I) is significantly hyperphosphorylated, and in vitro studies suggest that it enhances myofilament calcium sensitivity and alters calpain-mediated cTnI proteolysis. However, how its hyperphosphorylation affects cardiac function in vivo remains unknown. METHODS AND RESULTS: To address the question, 2 transgenic mouse models were generated: a phospho-mimetic cTnIS200D and a phospho-silenced cTnIS200A, each driven by the cardiomyocyte-specific α-myosin heavy chain promoter. Cardiac structure assessed by echocardiography and histology was normal in both transgenic models compared with littermate controls (n=5). Baseline in vivo hemodynamics and isolated muscle studies showed that cTnIS200D significantly prolonged relaxation and lowered left ventricular peak filling rate, whereas ejection fraction and force development were normal (n=5). However, with increased heart rate or ß-adrenergic stimulation, cTnIS200D mice had less enhanced ejection fraction or force development versus controls, whereas relaxation improved similarly to controls (n=5). By contrast, cTnIS200A was functionally normal both at baseline and under the physiological stresses. To test whether either mutation impacted cardiac response to ischemic stress, isolated hearts were subjected to ischemia/reperfusion. cTnIS200D were protected, recovering 88±8% of contractile function versus 35±15% in littermate controls and 28±8% in cTnIS200A (n=5). This was associated with less cTnI proteolysis in cTnIS200D hearts. CONCLUSIONS: Hyperphosphorylation of this serine in cTnI C terminus impacts heart function by depressing diastolic function at baseline and limiting systolic reserve under physiological stresses. However, paradoxically, it preserves heart function after ischemia/reperfusion injury, potentially by decreasing proteolysis of cTnI. |
[Mh] Termos MeSH primário: |
Insuficiência Cardíaca/metabolismo Hemodinâmica Contração Miocárdica Traumatismo por Reperfusão Miocárdica/metabolismo Troponina I/metabolismo Função Ventricular Esquerda
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[Mh] Termos MeSH secundário: |
Agonistas Adrenérgicos beta/farmacologia Animais Calpaína/metabolismo Modelos Animais de Doenças Predisposição Genética para Doença Insuficiência Cardíaca/genética Insuficiência Cardíaca/fisiopatologia Hemodinâmica/efeitos dos fármacos Preparação de Coração Isolado Masculino Camundongos Endogâmicos C57BL Camundongos Transgênicos Mutação Contração Miocárdica/efeitos dos fármacos Traumatismo por Reperfusão Miocárdica/genética Traumatismo por Reperfusão Miocárdica/fisiopatologia Traumatismo por Reperfusão Miocárdica/prevenção & controle Miofibrilas/metabolismo Cadeias Pesadas de Miosina/genética Fenótipo Fosforilação Regiões Promotoras Genéticas Domínios Proteicos Estabilidade Proteica Proteólise Recuperação de Função Fisiológica Serina Fatores de Tempo Troponina I/genética Função Ventricular Esquerda/efeitos dos fármacos
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[Pt] Tipo de publicação: | JOURNAL ARTICLE |
[Nm] Nome de substância:
| 0 (Adrenergic beta-Agonists); 0 (Myh6 protein, mouse); 0 (Troponin I); 452VLY9402 (Serine); EC 3.4.22.- (Calpain); EC 3.6.4.1 (Myosin Heavy Chains) |
[Em] Mês de entrada: | 1709 |
[Cu] Atualização por classe: | 171020 |
[Lr] Data última revisão:
| 171020 |
[Sb] Subgrupo de revista: | IM |
[Da] Data de entrada para processamento: | 170914 |
[St] Status: | MEDLINE |
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