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1.
Am J Physiol Heart Circ Physiol ; 294(1): H205-12, 2008 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-17965283

RESUMO

Increased signaling by G(i)-coupled receptors has been implicated in dilated cardiomyopathy. To investigate the mechanisms, we used transgenic mice that develop dilated cardiomyopathy after conditional expression of a cardiac-targeted G(i)-coupled receptor (Ro1). Activation of G(i) signaling by the Ro1 agonist spiradoline caused decreased cellular cAMP levels and bradycardia in Langendorff-perfused hearts. However, acute termination of Ro1 signaling with the antagonist nor-binaltorphimine did not reverse the Ro1-induced contractile dysfunction, indicating that Ro1 cardiomyopathy was not due to acute effects of receptor signaling. Early after initiation of Ro1 expression, there was a 40% reduction in the abundance of the sarcoplasmic reticulum Ca(2+)-ATPase (P < 0.05); thereafter, there was progressive impairment of both Ca(2+) handling and force development assessed with ventricular trabeculae. Six weeks after initiation of Ro1 expression, systolic Ca(2+) concentration was reduced to 0.61 +/- 0.08 vs. 0.91 +/- 0.07 microM for control (n = 6-8; P < 0.05), diastolic Ca(2+) concentration was elevated to 0.41 +/- 0.07 vs. 0.23 +/- 0.06 microM for control (n = 6-8; P < 0.01), and the decline phase of the Ca(2+) transient (time from peak to 50% decline) was slowed to 0.25 +/- 0.02 s vs. 0.13 +/- 0.02 s for control (n = 6-8; P < 0.01). Early after initiation of Ro1 expression, there was a ninefold elevation of matrix metalloproteinase-2 (P < 0.01), which is known to cause myofilament injury. Consistent with this, 6 wk after initiation of Ro1 expression, Ca(2+)-saturated myofilament force in skinned trabeculae was reduced to 21 +/- 2 vs. 38 +/- 0.1 mN/mm(2) for controls (n = 3; P < 0.01). Furthermore, electron micrographs revealed extensive myofilament damage. These findings may have implications for some forms of human heart failure in which increased activity of G(i)-coupled receptors leads to impaired Ca(2+) handling and myofilament injury, contributing to impaired ventricular pump function and heart failure.


Assuntos
Citoesqueleto de Actina/metabolismo , Cálcio/metabolismo , Cardiomiopatia Dilatada/metabolismo , Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/metabolismo , Miocárdio/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Receptores Opioides kappa/metabolismo , Transdução de Sinais , Citoesqueleto de Actina/ultraestrutura , Animais , Cardiomiopatia Dilatada/genética , Cardiomiopatia Dilatada/patologia , Cardiomiopatia Dilatada/fisiopatologia , AMP Cíclico/metabolismo , Metaloproteinase 2 da Matriz/metabolismo , Camundongos , Camundongos Transgênicos , Contração Miocárdica , Miocárdio/enzimologia , Miocárdio/ultraestrutura , Naltrexona/análogos & derivados , Naltrexona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Pirrolidinas/farmacologia , Receptores Acoplados a Proteínas G/efeitos dos fármacos , Receptores Acoplados a Proteínas G/genética , Receptores Opioides kappa/efeitos dos fármacos , Receptores Opioides kappa/genética , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fatores de Tempo , Função Ventricular Esquerda
2.
Biochem Biophys Res Commun ; 358(1): 189-95, 2007 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-17475219

RESUMO

Matrix metalloproteinases (MMPs) are central to the development and progression of dysfunctional ventricular remodeling after tissue injury. We studied 6 month old heterozygous mice with cardiac-specific transgenic expression of active MMP-2 (MMP-2 Tg). MMP-2 Tg hearts showed no substantial gross alteration of cardiac phenotype compared to age-matched wild-type littermates. However, buffer perfused MMP-2 Tg hearts subjected to 30 min of global ischemia followed by 30 min of reperfusion had a larger infarct size and greater depression in contractile performance compared to wild-type hearts. Importantly, cardioprotection mediated by ischemic preconditioning (IPC) was completely abolished in MMP-2 Tg hearts, as shown by abnormalities in mitochondrial ultrastructure and impaired respiration, increased lipid peroxidation, cell necrosis and persistently reduced recovery of contractile performance during post-ischemic reperfusion. We conclude that MMP-2 functions not only as a proteolytic enzyme but also as a previously unrecognized active negative regulator of mitochondrial function during superimposed oxidative stress.


Assuntos
Metaloproteinase 2 da Matriz/biossíntese , Mitocôndrias Cardíacas/fisiologia , Miocárdio/enzimologia , Animais , Creatina Quinase/metabolismo , Heterozigoto , Precondicionamento Isquêmico Miocárdico , Peroxidação de Lipídeos , Metaloproteinase 2 da Matriz/genética , Camundongos , Camundongos Transgênicos , Mitocôndrias Cardíacas/enzimologia , Contração Miocárdica , Infarto do Miocárdio/enzimologia , Infarto do Miocárdio/patologia , Infarto do Miocárdio/fisiopatologia , Traumatismo por Reperfusão Miocárdica/enzimologia , Traumatismo por Reperfusão Miocárdica/patologia , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Miocárdio/patologia , Miocárdio/ultraestrutura , Necrose
3.
Cardiovasc Res ; 69(3): 688-96, 2006 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-16183043

RESUMO

OBJECTIVE: Matrix metalloproteinase-2 (MMP-2) plays a major role in dysfunctional ventricular remodeling following myocardial injury induced by ischemia/reperfusion and heart failure. To directly assess the role of MMP-2 in the absence of superimposed injury, we generated cardiac-specific, constitutively active MMP-2 transgenic mice. METHODS: Morphologic and functional studies were carried out using both intact and demembranated (skinned) right ventricular trabeculae dissected from hearts of 8-month-old MMP-2 transgenic mice and wild-type controls (WT). RESULTS: Electron micrographs showed that compared to WT, MMP-2 myocardium had no gross, ultrastructural changes (no myocyte dropout or gross fibrosis). However, MMP-2 myocardium contained fibroblasts with abundant rough endoplasmic reticulum, consistent with an activated synthetic phenotype, suggesting extracellular matrix remodeling in MMP-2 trabeculae. Consistent with remodeling, mechanical studies found increased stiffness of intact unstimulated trabeculae (increasing sarcomere lengths from 2 to 2.3 microm caused a greater rise of passive muscle force for MMP-2 trabeculae versus WT). With electrical stimulation, MMP-2 trabeculae generated substantially less active force at all sarcomere lengths. Moreover, inotropic responses to increases of bath [Ca2+], pacing frequency, and isoproterenol were all significantly reduced versus WT trabeculae. Skinned fiber assessment of myofilament function revealed that maximum Ca2+-activated force of skinned MMP-2 trabeculae was reduced to approximately 50% of WT, suggesting a myofilament contraction defect. CONCLUSION: Cardiac-specific, constitutively active MMP-2 expression leads to impaired contraction and diminished responses to inotropic stimulation. These findings indicate that MMP-2 can directly impair ventricular function in the absence of superimposed injury.


Assuntos
Metaloproteinase 2 da Matriz/metabolismo , Miocárdio/enzimologia , Miocárdio/ultraestrutura , Citoesqueleto de Actina/ultraestrutura , Adenilil Ciclases/metabolismo , Antagonistas Adrenérgicos beta/farmacologia , Animais , Cálcio/metabolismo , Colforsina/farmacologia , Estimulação Elétrica , Retículo Endoplasmático/ultraestrutura , Fibroblastos/ultraestrutura , Técnicas In Vitro , Isoproterenol/farmacologia , Metaloproteinase 2 da Matriz/genética , Camundongos , Camundongos Transgênicos , Microscopia Eletrônica , Microscopia de Fluorescência , Contração Miocárdica , Miocárdio/metabolismo , Sarcômeros/ultraestrutura , Estimulação Química , Disfunção Ventricular Esquerda/enzimologia , Disfunção Ventricular Esquerda/fisiopatologia , Remodelação Ventricular
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