Overexpression Of Cardiomyocyte A Alpha(1a)-Adrenergic Receptors Attenuates Postinfarct Remodeling By Inducing Angiogenesis Through Heterocellular Signaling
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY(2015)
摘要
Objective Stimulation of cardiac (1A)-adrenergic receptors ((1A)-AR) has been proposed for treatment of heart failure, since it increases myocardial contractility. We investigated a different mechanism, induction of angiogenesis.Approach and Results Four to 6 weeks after permanent coronary artery occlusion, transgenic rats with cardiomyocyte-specific (1A)-adrenergic receptor overexpression had less remodeling than their nontransgenic littermates, with less fibrosis, hypertrophy and lung weight, and preserved left ventricular ejection fraction and wall stress (all P<0.05). Coronary blood flow, measured with microspheres, increased in the infarct zone in transgenic rats compared with nontransgenic littermates (1.40.2 versus 0.5 +/- 0.08 mL min(-1) g(-1); P<0.05), which is consistent with angiogenesis, as reflected by a 20% increase in capillary density in the zone adjacent to the infarct. The question arose, how does transgenic overexpression of a gene in cardiomyocytes induce angiogenesis? We identified a paracrine mechanism, whereby vascular endothelial growth factor-A mRNA and protein were increased in isolated transgenic cardiomyocytes and also by nontransgenic littermate cardiomyocytes treated with an (1A)-agonist, resulting in angiogenesis. Conditioned medium from cultured cardiomyocytes treated with an (1A) agonist enhanced human umbilical vein endothelial cell tubule formation, which was blocked by an anti-vascular endothelial growth factor-A antibody. Moreover, improved cardiac function, blood flow, and increased capillary density after chronic coronary artery occlusion in transgenic rats were blocked by either a mitogen ERK kinase (MEK) or a vascular endothelial growth factor-A inhibitor.Conclusion Cardiomyocyte-specific overexpression of the (1A)-adrenergic receptors resulted in enhanced MEK-dependent cardiomyocyte vascular endothelial growth factor-A expression, which stimulates angiogenesis via a paracrine mechanism involving heterocellular cardiomyocyte/endothelial cell signaling, protecting against remodeling and heart failure after chronic coronary artery occlusion.
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关键词
alpha adrenergic receptors,angiogenesis,heart failure,myocardial infarction,myocytes,cardiac,vascular endothelial growth factor
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