Chronic hypoxia differentially regulates α1-adrenergic receptor subtype mRNAs and inhibits α1-adrenergic receptor-stimulated cardiac hypertrophy and signaling

Academic Article

Abstract

  • Background: 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 α1-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 α1-AR-mediated signaling and α1-AR changes at both the protein and mRNA levels. Methods and Results: 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 α1-AR- transduced phosphatidylinositol hydrolysis, as indicated by a reduction in α1-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 α1-AR-mediated signaling and could result from changes in α1-AR numbers and/or subtype distribution. To address this issue, we determined α1-AR density and subtype distribution by radioligand binding and α1-AR subtype mRNAs, including α(1A/D)-, α(1B)-, and α(1C)-ARs, by RNase protection assays. We found that chronic hypoxia differentially regulated both the pharmacologically defined α1-AR subtypes and the mRNAs for the α1-AR subtypes. Thus, hypoxia for 72 hours coordinately downregulated both the pharmacologically defined α(1A)-AR density and the α(1C)-AR mRNA level. During normoxia, NE increased the pharmacologically defined α(1A)-AR density and the α(1C)-AR mRNA level, but hypoxia for 72 hours prevented these NE-mediated changes. Conclusions: Chronic hypoxia (1) inhibits α1-AR-mediated hypertrophy of cardiac myocytes and α1-AR-transduced phosphatidylinositol hydrolysis and (2) downregulates both the pharmacologically defined α(1A)-AR density and the α(1C)-AR mRNA levels.
  • Authors

    Digital Object Identifier (doi)

    Author List

  • Li HT; Long CS; Rokosh G; Honbo NY; Karliner JS
  • Start Page

  • 918
  • End Page

  • 925
  • Volume

  • 92
  • Issue

  • 4