Lymperopoulos Anastasios, Rengo Giuseppe, Funakoshi Hajime, Eckhart Andrea D, Koch Walter J
Center for Translational Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
Nat Med. 2007 Mar;13(3):315-23. doi: 10.1038/nm1553. Epub 2007 Feb 18.
Cardiac overstimulation by the sympathetic nervous system (SNS) is a salient characteristic of heart failure, reflected by elevated circulating levels of catecholamines. The success of beta-adrenergic receptor (betaAR) antagonists in heart failure argues for SNS hyperactivity being pathogenic; however, sympatholytic agents targeting alpha2AR-mediated catecholamine inhibition have been unsuccessful. By investigating adrenal adrenergic receptor signaling in heart failure models, we found molecular mechanisms to explain the failure of sympatholytic agents and discovered a new strategy to lower SNS activity. During heart failure, there is substantial alpha2AR dysregulation in the adrenal gland, triggered by increased expression and activity of G protein-coupled receptor kinase 2 (GRK2). Adrenal gland-specific GRK2 inhibition reversed alpha2AR dysregulation in heart failure, resulting in lowered plasma catecholamine levels, improved cardiac betaAR signaling and function, and increased sympatholytic efficacy of a alpha2AR agonist. This is the first demonstration, to our knowledge, of a molecular mechanism for SNS hyperactivity in heart failure, and our study identifies adrenal GRK2 activity as a new sympatholytic target.
交感神经系统（SNS）对心脏的过度刺激是心力衰竭的一个显著特征，表现为循环中儿茶酚胺水平升高。β-肾上腺素能受体（βAR）拮抗剂在心力衰竭治疗中的成功表明SNS功能亢进具有致病性；然而，针对α2AR介导的儿茶酚胺抑制作用的抗交感神经药物却未取得成功。通过研究心力衰竭模型中的肾上腺肾上腺素能受体信号传导，我们发现了解释抗交感神经药物失效的分子机制，并发现了一种降低SNS活性的新策略。在心力衰竭期间，肾上腺中存在大量α2AR失调，这是由G蛋白偶联受体激酶2（GRK2）表达和活性增加所引发的。肾上腺特异性GRK2抑制可逆转心力衰竭时的α2AR失调，导致血浆儿茶酚胺水平降低、心脏βAR信号传导和功能改善，以及α2AR激动剂的抗交感神经功效增强。据我们所知，这是首次证明心力衰竭中SNS功能亢进的分子机制，我们的研究将肾上腺GRK2活性确定为一个新的抗交感神经靶点。
