RESUMO
A pathologic osteochondrogenic differentiation of vascular smooth muscle cells (VSMCs) promotes arterial calcifications, a process associated with significant morbidity and mortality. The molecular pathways promoting this pathology are not completely understood. We studied VSMCs, mouse aortic rings, and human aortic valves and showed here that histone deacetylase 4 (HDAC4) is upregulated early in the calcification process. Gain- and loss-of-function assays demonstrate that HDAC4 is a positive regulator driving this pathology. HDAC4 can shuttle between the nucleus and cytoplasm, but in VSMCs, the cytoplasmic rather than the nuclear activity of HDAC4 promotes calcification, and a nuclear-localized mutant of HDAC4 fails to promote calcification. The cytoplasmic location and function of HDAC4 is controlled by the activity of salt-inducible kinase (SIK). Pharmacologic inhibition of SIK sends HDAC4 to the nucleus and inhibits the calcification process in VSMCs, aortic rings, and in vivo In the cytoplasm, HDAC4 binds and its activity depends on the adaptor protein ENIGMA (Pdlim7) to promote vascular calcification. These results establish a cytoplasmic role for HDAC4 and identify HDAC4, SIK, and ENIGMA as mediators of vascular calcification.
Assuntos
Regulação da Expressão Gênica , Histona Desacetilases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Tirosina Quinases/metabolismo , Proteínas Repressoras/genética , Calcificação Vascular/fisiopatologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Valva Aórtica/fisiopatologia , Diferenciação Celular , Núcleo Celular , Citoplasma/química , Citoplasma/metabolismo , Proteínas do Citoesqueleto/genética , Histona Desacetilases/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas com Domínio LIM/genética , Camundongos , Músculo Liso Vascular/patologia , Proteínas Serina-Treonina Quinases/genética , Proteínas Tirosina Quinases/genética , Proteínas Repressoras/metabolismo , Transdução de Sinais , Regulação para Cima , Calcificação Vascular/genéticaRESUMO
Heart failure is a major public health problem in western society. Recently, agents that inhibit histone deacetylase (HDAC) enzymes were developed and approved by the FDA as anticancer agents. This breakthrough has provided the motivation to develop more potent and more selective HDAC inhibitors and to target other pathologic conditions with these drugs. Here we review experimental evidence showing that these drugs may be beneficial in preventing cardiac hypertrophy and heart failure. Several lines of evidence show that inhibitors of Class I HDACs can blunt cardiac hypertrophy and preserve cardiac function in several small animal models. In contrast, Class IIa HDACs appear to be suppressors of hypertrophy, though experimental data with small molecule blockers of this class is largely lacking. The effects of HDAC inhibition in cardiac diseases, the cell population in the heart that is targeted by HDAC blockers, as well as the relative roles of specific HDACs are still under intense investigation.