RESUMEN
Polo-like kinase 1 (PLK1), an essential regulator of cell division, is currently undergoing clinical evaluation as a target for cancer therapy. We report an unexpected function of Plk1 in sustaining cardiovascular homeostasis. Plk1 haploinsufficiency in mice did not induce obvious cell proliferation defects but did result in arterial structural alterations, which frequently led to aortic rupture and death. Specific ablation of Plk1 in vascular smooth muscle cells (VSMCs) led to reduced arterial elasticity, hypotension, and an impaired arterial response to angiotensin II in vivo. Mechanistically, we found that Plk1 regulated angiotensin II-dependent activation of RhoA and actomyosin dynamics in VSMCs in a mitosis-independent manner. This regulation depended on Plk1 kinase activity, and the administration of small-molecule Plk1 inhibitors to angiotensin II-treated mice led to reduced arterial fitness and an elevated risk of aneurysm and aortic rupture. We thus conclude that a partial reduction of Plk1 activity that does not block cell division can nevertheless impair aortic homeostasis. Our findings have potentially important implications for current approaches aimed at PLK1 inhibition for cancer therapy.
Asunto(s)
Angiotensina II/metabolismo , Aneurisma de la Aorta/genética , Rotura de la Aorta/genética , Proteínas de Ciclo Celular/genética , Músculo Liso Vascular/metabolismo , Miocitos del Músculo Liso/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Proteínas Proto-Oncogénicas/genética , Proteínas de Unión al GTP rho/metabolismo , Animales , Aorta/metabolismo , Aorta/ultraestructura , Aneurisma de la Aorta/metabolismo , Rotura de la Aorta/metabolismo , Presión Sanguínea , Proteínas de Ciclo Celular/antagonistas & inhibidores , Proteínas de Ciclo Celular/metabolismo , Proliferación Celular/genética , Técnica del Anticuerpo Fluorescente , Técnicas de Silenciamiento del Gen , Haploinsuficiencia , Homeostasis/genética , Hipotensión/genética , Immunoblotting , Ratones , Microscopía Electrónica de Transmisión , Mitosis , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa , Rigidez Vascular/genética , Proteína de Unión al GTP rhoA , Quinasa Tipo Polo 1RESUMEN
The activin receptor-like kinase 1 (ALK-1) is a type I cell-surface receptor for the transforming growth factor-ß (TGF-ß) family of proteins. Hypertension is related to TGF-ß1, because increased TGF-ß1 expression is correlated with an elevation in arterial pressure (AP) and TGF-ß expression is upregulated by the renin-angiotensin-aldosterone system. The purpose of this study was to assess the role of ALK-1 in regulation of AP using Alk1 haploinsufficient mice (Alk1(+/-)). We observed that systolic and diastolic AP were significantly higher in Alk1(+/-) than in Alk1(+/+) mice, and all functional and structural cardiac parameters (echocardiography and electrocardiography) were similar in both groups. Alk1(+/-) mice showed alterations in the circadian rhythm of AP, with higher AP than Alk1(+/+) mice during most of the light period. Higher AP in Alk1(+/-) mice is not a result of a reduction in the NO-dependent vasodilator response or of overactivation of the peripheral renin-angiotensin system. However, intracerebroventricular administration of losartan had a hypotensive effect in Alk1(+/-) and not in Alk1(+/+) mice. Alk1(+/-) mice showed a greater hypotensive response to the ß-adrenergic antagonist atenolol and higher concentrations of epinephrine and norepinephrine in plasma than Alk1(+/+) mice. The number of brain cholinergic neurons in the anterior basal forebrain was reduced in Alk1(+/-) mice. Thus, we concluded that the ALK-1 receptor is involved in the control of AP, and the high AP of Alk1(+/-) mice is explained mainly by the sympathetic overactivation shown by these animals, which is probably related to the decreased number of cholinergic neurons.
