Alpha–1-Adrenergic Receptor Subtypes in Human Heart Failure

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Introduction: Extensive data from cell and animal studies suggest that alpha–1-adrenergic receptors (α1-ARs) play adaptive roles in the heart. α1-ARs exist as three distinct subtypes: A, B, and D. The mouse myocardium contains α1A and α1B and there is evidence that each subtype mediates separate beneficial pathways that protect against heart failure (HF). Very little is known about α1-AR subtype expression in the human heart. Hypothesis: This study tests the hypothesis that α1-AR abundance is maintained in the setting of HF. Methods: Failing (F) human hearts [n=12; mean EF 24%; mean age 44; 75% male; 8 non-ischemic, 4 ischemic] were obtained after cardioplegia during heart transplant. Non-failing (NF) controls were unused donor hearts [n=9; mean EF 59%; mean age 43; 67% male]. α1-AR mRNAs from left ventricular (LV) myocardium were quantified by quantitative real-time reverse transcription PCR (qRT-PCR) and were normalized to β-actin and TATA-binding protein. Saturation binding used 3H-prazosin for α1-ARs and and 125I-cyanopindolol for β-ARs. α1-AR competition binding used 5-methylurapidil (5-MU) for the α1A and BMY–7378 for the α1D. Results: α1-AR protein abundance was unchanged in HF [NF: 4.3±0.6 fmol/mg protein vs. F: 4.7±0.6 fmol/mg protein]. There was a trend toward increased total α1-AR mRNA abundance in HF [NF: 92±5 Arbitrary Units (AU) vs. F: 118±12 AU, p=0.09]. There was no change in α1A [NF: 41% vs. F: 38%] or α1B [NF: 59% vs. F: 62%] protein levels, but α1A mRNA levels were increased in HF [NF: 56±9 AU vs. F: 80±10 AU, p=0.04]. β-AR abundance was decreased in HF [NF: 37±6 fmol/mg protein vs. F: 21±4 fmol/mg protein] and the ratio of α1/β-ARs increased [NF mRNA: 11% vs F mRNA: 19%; NF binding: 12% vs F binding: 22%]. β-blocker therapy did not affect these changes. Conclusions: This is the first measurement of α1-AR subtype proteins in the human heart and the most extensive evaluation of the changes in myocardial α1-AR subtypes in the setting of HF. In mouse models, the α1A has been shown to protect against the development of HF. These data indicate that the α1A is not downregulated in failing human myocardium and might be a target for agonist therepy in the treatment of HF.