+ Site Statistics
+ Search Articles
+ PDF Full Text Service
How our service works
Request PDF Full Text
+ Follow Us
Follow on Facebook
Follow on Twitter
Follow on LinkedIn
+ Subscribe to Site Feeds
Most Shared
PDF Full Text
+ Translate
+ Recently Requested

Chronic hypoxia differentially regulates alpha 1-adrenergic receptor subtype mRNAs and inhibits alpha 1-adrenergic receptor-stimulated cardiac hypertrophy and signaling



Chronic hypoxia differentially regulates alpha 1-adrenergic receptor subtype mRNAs and inhibits alpha 1-adrenergic receptor-stimulated cardiac hypertrophy and signaling



Circulation 92(4): 918-925



After myocardial ischemia and/or infarction, surviving cardiac myocytes in and around the injured zone develop hypertrophy to compensate for the loss of contractile units due to myocyte injury and death. One of the factors that may be involved in the development of hypertrophy after ischemic injury is norepinephrine (NE), an agent that induces hypertrophy of cardiac myocytes through the alpha 1-adrenergic receptor (AR). It is not known, however, whether hypoxia, a major component of ischemia, has any direct effect on NE-stimulated hypertrophy. Therefore, we sought to determine whether chronic hypoxia could alter NE-stimulated hypertrophy and if so, whether this alteration was related to alpha 1-AR-mediated signaling and alpha 1-AR changes at both the protein and mRNA levels. We developed a model of chronic hypoxia in cultured neonatal rat cardiac myocytes in which myocytes were exposed to 1% oxygen for 72 hours. Initially, we observed that chronic hypoxia inhibited NE-stimulated hypertrophy, as reflected by decreases in both new protein synthesis and total protein content during chronic hypoxia. Then we found that chronic hypoxia also inhibited alpha 1-AR-transduced phosphatidylinositol hydrolysis, as indicated by a reduction in alpha 1-AR-stimulated inositol phosphate production in hypoxic cells. These observations suggested that the inhibition of NE-stimulated hypertrophy seen during chronic hypoxia was due to impairment of alpha 1-AR-mediated signaling and could result from changes in alpha 1-AR numbers and/or subtype distribution. To address this issue, we determined alpha 1-AR density and subtype distribution by radioligand binding and alpha 1-AR subtype mRNAs, including alpha 1A/D-, alpha 1B-, and alpha 1C-ARs, by RNase protection assays. We found that chronic hypoxia differentially regulated both the pharmacologically defined alpha 1-AR subtypes and the mRNAs for the alpha 1-AR subtypes. Thus, hypoxia for 72 hours coordinately downregulated both the pharmacologically defined alpha 1A-AR density and the alpha 1C-AR mRNA level. During normoxia, NE increased the pharmacologically defined alpha 1A-AR density and the alpha 1C-AR mRNA level, but hypoxia for 72 hours prevented these NE-mediated changes. Chronic hypoxia (1) inhibits alpha 1-AR-mediated hypertrophy of cardiac myocytes and alpha 1-AR-transduced phosphatidylinositol hydrolysis and (2) downregulates both the pharmacologically defined alpha 1A-AR density and the alpha 1C-AR mRNA level.

Please choose payment method:






(PDF emailed within 1 workday: $29.90)

Accession: 042538699

Download citation: RISBibTeXText

PMID: 7641375


Related references

Rapamycin inhibits alpha 1-adrenergic receptor-stimulated cardiac myocyte hypertrophy but not activation of hypertrophy-associated genes. Evidence for involvement of p70 S6 kinase. Circulation Research 81(2): 176-186, 1997

Differential regulation of cardiac beta-1-and alpha-1-adrenergic receptor mRNAs by chronic hypoxia. Circulation 92(8 Suppl. ): I236, 1995

A1-adrenergic receptor subtype mRNAs are differentially regulated by a1-adrenergic and other hypertrophic stimuli in cardiac myocytes in culture and in vivo. Repression of a1B and a1D but induction of a1C. The Journal of Biological Chemistry 271: 39-43, 1996

Glycogen phosphorylase activation by two different alpha 1-adrenergic receptor subtypes: methoxamine selectively stimulates a putative alpha 1-adrenergic receptor subtype (alpha 1a) that couples with Ca2+ influx. Molecular Pharmacology 36(1): 166-176, 1989

Decrease in beta 1-adrenergic and M2-muscarinic receptor mRNA levels and unchanged accumulation of mRNAs coding for G alpha i-2 and G alpha s proteins in rat cardiac hypertrophy. Journal of Molecular and Cellular Cardiology 27(10): 2287-2294, 1995

Expression of alpha 1-adrenergic receptor subtype mRNA in rat tissues and human SK-N-MC neuronal cells: implications for alpha 1-adrenergic receptor subtype classification. Molecular Pharmacology 46(2): 221-226, 1994

Selective activation of alpha1A-adrenergic receptors in neonatal cardiac myocytes is sufficient to cause hypertrophy and differential regulation of alpha1-adrenergic receptor subtype mRNAs. Journal of Molecular and Cellular Cardiology 30(8): 1515-1523, 1998

Developmental expression of the alpha-1A, alpha-1B and alpha-1C adrenergic receptor subtype mRNAs in the rat brain. Society for Neuroscience Abstracts 18(1-2): 457, 1992

Inhibition of p70 S6 kinase inhibits alpha-1-adrenergic receptor stimulated cardiomyocyte hypertrophy. Medicine & Science in Sports & Exercise 27(5 Suppl. ): S124, 1995

Expansion of the alpha 2-adrenergic receptor family: cloning and characterization of a human alpha 2-adrenergic receptor subtype, the gene for which is located on chromosome 2. Proceedings of the National Academy of Sciences of the United States of America 87(13): 5094-5098, 1990

Alpha 2-adrenergic receptor subtypes: subtle mutation of the alpha 2A-adrenergic receptor in vivo by gene targeting strategies reveals the role of this subtype in multiple physiological settings. Recent Progress in Hormone Research 53: 25-42, 1998

Expression of alpha-1- and alpha-2-adrenergic receptor subtype mRNAs in human cerebellum. Society for Neuroscience Abstracts 23(1-2): 2323, 1997

Alpha1-adrenergic receptor subtype mRNAs are differentially regulated by alpha1-adrenergic and other hypertrophic stimuli in cardiac myocytes in culture and in vivo. Repression of alpha1B and alpha1D but induction of alpha1C. Journal of Biological Chemistry 271(10): 5839-5843, 1996

Cross talk between angiotensin AT1 and alpha 1-adrenergic receptors: angiotensin II downregulates alpha 1a-adrenergic receptor subtype mRNA and density in neonatal rat cardiac myocytes. Circulation Research 81(3): 396-403, 1997

Multiple alpha 2 adrenergic receptor subtypes. I. Comparison of [3H]RX821002-labeled rat R alpha-2A adrenergic receptors in cerebral cortex to human H alpha2A adrenergic receptor and other populations of alpha-2 adrenergic subtypes. Journal of Pharmacology and Experimental Therapeutics 270(3): 946-957, 1994