Overexpression of Cardiomyocyte α1A-Adrenergic Receptors Attenuates Postinfarct Remodeling by Inducing Angiogenesis Through Heterocellular Signaling.
OBJECTIVE
Stimulation of cardiac α1A-adrenergic receptors (α1A-AR) has been proposed for treatment of heart failure, since it increases myocardial contractility. We investigated a different mechanism, induction of angiogenesis.


RESULTS
Four to 6 weeks after permanent coronary artery occlusion, transgenic rats with cardiomyocyte-specific α1A-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 (1.4±0.2 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 α1A-agonist, resulting in angiogenesis. Conditioned medium from cultured cardiomyocytes treated with an α1A 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.


CONCLUSIONS
Cardiomyocyte-specific overexpression of the α1A-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.
From the Cardiovascular Research Institute, Department of Cell Biology and Molecular Medicine, Rutgers-New Jersey Medical School, Newark (X.Z., R.P., D.E.V., S.F.V.); and Victor Chang Cardiac Research Institute and Faculty of Medicine and Life Sciences, University of New South Wales, Sydney, New South Wales, Australia (P.B., D.M.B., R.M.G.).
Xin
X
Zhao
From the Cardiovascular Research Institute, Department of Cell Biology and Molecular Medicine, Rutgers-New Jersey Medical School, Newark (X.Z., R.P., D.E.V., S.F.V.); and Victor Chang Cardiac Research Institute and Faculty of Medicine and Life Sciences, University of New South Wales, Sydney, New South Wales, Australia (P.B., D.M.B., R.M.G.).
Poornima
P
Balaji
From the Cardiovascular Research Institute, Department of Cell Biology and Molecular Medicine, Rutgers-New Jersey Medical School, Newark (X.Z., R.P., D.E.V., S.F.V.); and Victor Chang Cardiac Research Institute and Faculty of Medicine and Life Sciences, University of New South Wales, Sydney, New South Wales, Australia (P.B., D.M.B., R.M.G.).
Ronald
R
Pachon
From the Cardiovascular Research Institute, Department of Cell Biology and Molecular Medicine, Rutgers-New Jersey Medical School, Newark (X.Z., R.P., D.E.V., S.F.V.); and Victor Chang Cardiac Research Institute and Faculty of Medicine and Life Sciences, University of New South Wales, Sydney, New South Wales, Australia (P.B., D.M.B., R.M.G.).
Daniella M
DM
Beniamen
From the Cardiovascular Research Institute, Department of Cell Biology and Molecular Medicine, Rutgers-New Jersey Medical School, Newark (X.Z., R.P., D.E.V., S.F.V.); and Victor Chang Cardiac Research Institute and Faculty of Medicine and Life Sciences, University of New South Wales, Sydney, New South Wales, Australia (P.B., D.M.B., R.M.G.).
Dorothy E
DE
Vatner
From the Cardiovascular Research Institute, Department of Cell Biology and Molecular Medicine, Rutgers-New Jersey Medical School, Newark (X.Z., R.P., D.E.V., S.F.V.); and Victor Chang Cardiac Research Institute and Faculty of Medicine and Life Sciences, University of New South Wales, Sydney, New South Wales, Australia (P.B., D.M.B., R.M.G.).
Robert M
RM
Graham
From the Cardiovascular Research Institute, Department of Cell Biology and Molecular Medicine, Rutgers-New Jersey Medical School, Newark (X.Z., R.P., D.E.V., S.F.V.); and Victor Chang Cardiac Research Institute and Faculty of Medicine and Life Sciences, University of New South Wales, Sydney, New South Wales, Australia (P.B., D.M.B., R.M.G.). vatnersf@njms.rutgers.edu b.graham@victorchang.edu.au.
Stephen F
SF
Vatner
D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005355:Fibrosis; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D008822:Mice, Transgenic; D009200:Myocardial Contraction; D009203:Myocardial Infarction / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D018919:Neovascularization, Physiologic; D019899:Paracrine Communication; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017207:Rats, Sprague-Dawley; D055647:Rats, Transgenic; D018340:Receptors, Adrenergic, alpha-1 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013318:Stroke Volume; D013997:Time Factors; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000378:metabolism; D016277:Ventricular Function, Left; D020257:Ventricular Remodeling
D020533:Angiogenesis Inhibitors; D047428:Protein Kinase Inhibitors; D018340:Receptors, Adrenergic, alpha-1; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; C467498:vascular endothelial growth factor A, rat; D020930:MAP Kinase Kinase Kinases
alpha adrenergic receptors; angiogenesis; cardiac; heart failure; myocardial infarction; myocytes; vascular endothelial growth factor