Clinical & Experimental Cardiology
Open Access
ISSN: 2155-9880
+44 1300 500008
ISSN: 2155-9880
+44 1300 500008
Anush Oganesian
Scientific Tracks Abstracts: J Clin Exp Cardiolog
Various cardiovascular disorders, such as hypertension and heart failure, are associated with polymorphisms in genes involved in the regulation of adrenergic system, mostly beta-Adrenergic Receptors (AR) and alpha2ARs. Three alpha1AR (α1AR) subtypes have been characterized and are expressed in human heart and vessels (α1a, α1b, α1d), mediating actions of the sympathetic nervous system through binding of the endogenous catecholamines epinephrine and norepinephrine. The predominant subtype in human vessels and heart is α1aAR. A few studies have reported an association between α1aAR polymorphisms with hypertension and heart failure in humans. Previously 9 naturally occurring human SNPs in the α1aAR coding region have been identified and pharmacologically characterized. The α1aAR-G247R (α1a-247R) SNP present in the third intracellular loop of the α1aAR was identified in a patient with severe hypertension. Several reports also suggest that specific α1aAR genetic variants are associated with human hypertension. We therefore explored whether there are unique molecular mechanisms that might account for this association. We recently reported that α1a-247R confers proliferative advantage to fibroblasts cultured under serum-deprived conditions and importantly, in the absence of agonist stimulation. Our results suggest that increased cell proliferation triggered by the naturally occurring human genetic variant α1aAR-G247R is due to intrinsic MMP-7 and ADAM- 12 dependent activation of an autocrine loop leading to constitutive production of HB-EGF and transactivation of EGFR in the absence of agonist. These findings provide the first evidence for a novel mechanism of sympathetically-mediated human hypertension triggered by a naturally occurring human genetic variant, α1a-247R activated signal transduction pathway. We also study the constitutive and agonist-induced biological effects of this SNP and the signaling pathways activated in cardiomyoblasts. We show that cardiomyoblasts expressing α1a-247R exhibit increased proliferation without agonist stimulation, undergo hypertrophy upon agonist stimulation, and change the cell morphology and phenotype to highly proliferative, fibroblast-like cells. These data confirm our previous findings that agonist-and serum-independent EGFR transactivation leading to enhanced proliferation of fibroblasts expressing α1a-247R is not cell type dependent but generalizable phenomena. Our observations also suggest that this SNP may lead to changes of vessel and heart structure, and lead to cardiovascular disease. These findings also raise the tantalizing hypothesis that a naturally occurring α1aAR genetic variant may be mechanistically involved in some forms of human hypertension, and that MMP/ADAM-specific inhibitors may be effective therapeutic agents for treatment of some forms of sympathetically-mediated human hypertension
Anush Oganesian is a Research Assistant Professor in the Department of Anesthesiology at the University of Washington. She received her BS/ MS in Molecular Biology/Chemistry from the Yerevan University in Armenia and her Ph.D. in Biochemistry/Organic Chemistry from the Institute of Element Organic Compounds, Academy of Sciences in Moscow, Russia. Anush did her post-doctorial training at the University of Washington with Linda Sandell in the Department of Orthopedics studying the extracellular matrix proteins including the N-propeptide of type IIA procollagen and its interaction with TGF�1 and BMP-2 proteins. She continued her postdoctoral training in the laboratory of Daniel Bowen-Pope in the Department of Pathology focusing on biochemical characterization, functional studies and signal transduction pathways regulated by PTPRQ and Phogrin, novel transmembrane protein tyrosine phosphatases with PTEN-like lipid-phosphatase activities