RESUMO
Aortic intramural hematoma (IMH) can evolve toward reabsorption, dissection or aneurysm. Hypertension is the most common predisposing factor in IMH and aneurysm patients, and the hypertensive mediator angiotensin-II induces both in mice. We have previously shown that constitutive deletion of Rcan1 isoforms prevents Angiotensin II-induced aneurysm in mice. Here we generate mice conditionally lacking each isoform or all isoforms in vascular smooth muscle cells, endothelial cells, or ubiquitously, to determine the contribution to aneurysm development of Rcan1 isoforms in vascular cells. Surprisingly, conditional Rcan1 deletion in either vascular cell-type induces a hypercontractile phenotype and aortic medial layer disorganization, predisposing to hypertension-mediated aortic rupture, IMH, and aneurysm. These processes are blocked by ROCK inhibition. We find that Rcan1 associates with GSK-3ß, whose inhibition decreases myosin activation. Our results identify potential therapeutic targets for intervention in IMH and aneurysm and call for caution when interpreting phenotypes of constitutively and inducibly deficient mice.
Assuntos
Dissecção Aórtica/genética , Ruptura Aórtica/genética , Glicogênio Sintase Quinase 3 beta/genética , Hematoma/genética , Hipertensão/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas Musculares/genética , Quinases Associadas a rho/genética , Dissecção Aórtica/metabolismo , Dissecção Aórtica/patologia , Dissecção Aórtica/prevenção & controle , Animais , Anti-Hipertensivos/farmacologia , Aorta/efeitos dos fármacos , Aorta/metabolismo , Aorta/patologia , Ruptura Aórtica/metabolismo , Ruptura Aórtica/patologia , Ruptura Aórtica/prevenção & controle , Proteínas de Ligação ao Cálcio , Modelos Animais de Doenças , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Deleção de Genes , Regulação da Expressão Gênica , Predisposição Genética para Doença , Glicogênio Sintase Quinase 3 beta/antagonistas & inibidores , Glicogênio Sintase Quinase 3 beta/metabolismo , Hematoma/metabolismo , Hematoma/patologia , Hematoma/prevenção & controle , Humanos , Hipertensão/tratamento farmacológico , Hipertensão/metabolismo , Hipertensão/patologia , Peptídeos e Proteínas de Sinalização Intracelular/deficiência , Masculino , Camundongos , Camundongos Knockout , Proteínas Musculares/deficiência , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Cultura Primária de Células , Isoformas de Proteínas/deficiência , Isoformas de Proteínas/genética , Inibidores de Proteínas Quinases/farmacologia , Quinases Associadas a rho/antagonistas & inibidores , Quinases Associadas a rho/metabolismoRESUMO
Heart muscle maintains blood circulation, while skeletal muscle powers skeletal movement. Despite having similar myofibrilar sarcomeric structures, these striated muscles differentially express specific sarcomere components to meet their distinct contractile requirements. The mechanism responsible is still unclear. We show here that preservation of the identity of the two striated muscle types depends on epigenetic repression of the alternate lineage gene program by the chromatin remodeling complex Chd4/NuRD. Loss of Chd4 in the heart triggers aberrant expression of the skeletal muscle program, causing severe cardiomyopathy and sudden death. Conversely, genetic depletion of Chd4 in skeletal muscle causes inappropriate expression of cardiac genes and myopathy. In both striated tissues, mitochondrial function was also dependent on the Chd4/NuRD complex. We conclude that an epigenetic mechanism controls cardiac and skeletal muscle structural and metabolic identities and that loss of this regulation leads to hybrid striated muscle tissues incompatible with life.