RESUMEN
Thoracic aortic aneurysm, as occurs in Marfan syndrome, is generally asymptomatic until dissection or rupture, requiring surgical intervention as the only available treatment. Here, we show that nitric oxide (NO) signaling dysregulates actin cytoskeleton dynamics in Marfan Syndrome smooth muscle cells and that NO-donors induce Marfan-like aortopathy in wild-type mice, indicating that a marked increase in NO suffices to induce aortopathy. Levels of nitrated proteins are higher in plasma from Marfan patients and mice and in aortic tissue from Marfan mice than in control samples, indicating elevated circulating and tissue NO. Soluble guanylate cyclase and cGMP-dependent protein kinase are both activated in Marfan patients and mice and in wild-type mice treated with NO-donors, as shown by increased plasma cGMP and pVASP-S239 staining in aortic tissue. Marfan aortopathy in mice is reverted by pharmacological inhibition of soluble guanylate cyclase and cGMP-dependent protein kinase and lentiviral-mediated Prkg1 silencing. These findings identify potential biomarkers for monitoring Marfan Syndrome in patients and urge evaluation of cGMP-dependent protein kinase and soluble guanylate cyclase as therapeutic targets.
Asunto(s)
Aneurisma de la Aorta Torácica/patología , Proteína Quinasa Dependiente de GMP Cíclico Tipo I/metabolismo , Síndrome de Marfan/complicaciones , Guanilil Ciclasa Soluble/metabolismo , Animales , Aorta/citología , Aorta/diagnóstico por imagen , Aorta/efectos de los fármacos , Aorta/patología , Aneurisma de la Aorta Torácica/diagnóstico , Aneurisma de la Aorta Torácica/etiología , Aneurisma de la Aorta Torácica/prevención & control , Biomarcadores/sangre , Biomarcadores/metabolismo , Carbazoles/administración & dosificación , GMP Cíclico/sangre , GMP Cíclico/metabolismo , Modelos Animales de Enfermedad , Femenino , Fibrilina-1/genética , Técnicas de Silenciamiento del Gen , Humanos , Masculino , Síndrome de Marfan/sangre , Síndrome de Marfan/genética , Síndrome de Marfan/patología , Ratones , Músculo Liso Vascular/citología , Mutación , Miocitos del Músculo Liso , Óxido Nítrico/metabolismo , Donantes de Óxido Nítrico/administración & dosificación , Cultivo Primario de Células , Guanilil Ciclasa Soluble/antagonistas & inhibidores , UltrasonografíaRESUMEN
Cardiovascular disease (CVD) is the leading cause of mortality in the world, with most CVD-related deaths resulting from myocardial infarction or stroke. The main underlying cause of thrombosis and cardiovascular events is atherosclerosis, an inflammatory disease that can remain asymptomatic for long periods. There is an urgent need for therapeutic and diagnostic options in this area. Atherosclerotic plaques contain autoantibodies1,2, and there is a connection between atherosclerosis and autoimmunity3. However, the immunogenic trigger and the effects of the autoantibody response during atherosclerosis are not well understood3-5. Here we performed high-throughput single-cell analysis of the atherosclerosis-associated antibody repertoire. Antibody gene sequencing of more than 1,700 B cells from atherogenic Ldlr-/- and control mice identified 56 antibodies expressed by in-vivo-expanded clones of B lymphocytes in the context of atherosclerosis. One-third of the expanded antibodies were reactive against atherosclerotic plaques, indicating that various antigens in the lesion can trigger antibody responses. Deep proteomics analysis identified ALDH4A1, a mitochondrial dehydrogenase involved in proline metabolism, as a target antigen of one of these autoantibodies, A12. ALDH4A1 distribution is altered during atherosclerosis, and circulating ALDH4A1 is increased in mice and humans with atherosclerosis, supporting the potential use of ALDH4A1 as a disease biomarker. Infusion of A12 antibodies into Ldlr-/- mice delayed plaque formation and reduced circulating free cholesterol and LDL, suggesting that anti-ALDH4A1 antibodies can protect against atherosclerosis progression and might have therapeutic potential in CVD.