RESUMO
BACKGROUND: Tenascin-C (TN-C) plays a maladaptive role in left ventricular (LV) hypertrophy following pressure overload. However, the role of TN-C in LV regression following mechanical unloading is unknown. METHODS: LV hypertrophy was induced by transverse aortic constriction for 10 weeks followed by debanding for 2 weeks in wild type (Wt) and TN-C knockout (TN-C KO) mice. Cardiac function was assessed by serial magnetic resonance imaging. The expression of fibrotic markers and drivers (angiotensin-converting enzyme-1, ACE-1) was determined in LV tissue as well as human cardiac fibroblasts (HCFs) after TN-C treatment. RESULTS: Chronic pressure overload resulted in a significant decline in cardiac function associated with LV dilation as well as upregulation of TN-C, collagen 1 (Col 1), and ACE-1 in Wt as compared to TN-C KO mice. Reverse remodeling in Wt mice partially improved cardiac function and fibrotic marker expression; however, TN-C protein expression remained unchanged. In HCF, TN-C strongly induced the upregulation of ACE 1 and Col 1. CONCLUSIONS: Pressure overload, when lasting long enough to induce HF, has less potential for reverse remodeling in mice. This may be due to significant upregulation of TN-C expression, which stimulates ACE 1, Col 1, and alpha-smooth muscle actin (α-SMA) upregulation in fibroblasts. Consequently, addressing TN-C in LV hypertrophy might open a new window for future therapeutics.
Assuntos
Aorta/fisiologia , Tenascina/metabolismo , Remodelação Ventricular , Animais , Fator Natriurético Atrial/genética , Fator Natriurético Atrial/metabolismo , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Constrição Patológica , Fibroblastos/metabolismo , Ventrículos do Coração/metabolismo , Humanos , Imageamento por Ressonância Magnética , Masculino , Camundongos , Camundongos Knockout , Peptidil Dipeptidase A/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Volume Sistólico , Função VentricularRESUMO
BACKGROUND: Vascular stiffness and endothelial dysfunction are accelerated by acute myocardial infarction (AMI) and subsequently increase the risk for recurrent coronary events. AIM: To explore whether remote ischemic perconditioning (RIPerc) protects against coronary and aorta endothelial dysfunction as well as aortic stiffness following AMI. METHODS: Male OFA-1 rats were subjected to 30 min of occlusion of the left anterior descending artery (LAD) followed by reperfusion either 3 or 28 days with or without RIPerc. Three groups: (1) sham operated (Sham, without LAD occlusion); (2) myocardial ischemia and reperfusion (MIR) and (3) MIR + RIPerc group with 3 cycles of 5 minutes of IR on hindlimb performed during myocardial ischemia were used. Assessment of vascular reactivity in isolated septal coronary arteries (non-occluded) and aortic rings as well as aortic stiffness was assessed by wire myography either 3 or 28 days after AMI, respectively. Markers of pro-inflammatory cytokines, adhesion molecules were assessed by RT-qPCR and ELISA. RESULTS: MIR promotes impaired endothelial-dependent relaxation in septal coronary artery segments, increased aortic stiffness and adverse left ventricular remodeling. These changes were markedly attenuated in rats treated with RIPerc and associated with a significant decline in P-selectin, IL-6 and TNF-α expression either in infarcted or non-infarcted myocardial tissue samples. CONCLUSIONS: Our study for the first time demonstrated that RIPerc alleviates MIR-induced coronary artery endothelial dysfunction in non-occluded artery segments and attenuates aortic stiffness in rats. The vascular protective effects of RIPerc are associated with ameliorated inflammation and might therefore be caused by reduced inflammatory signaling.