Cardiac Sympathetic Rejuvenation: A Link Between Nerve Function and Cardiac Hypertrophy

• Published in: Circulation research 2007-06, Vol.100 (12), p.1755-1764
• Main Authors: Kimura, Kensuke, Ieda, Masaki, Kanazawa, Hideaki, Yagi, Takashi, Tsunoda, Makoto, Ninomiya, Shin-ichi, Kurosawa, Hiroyuki, Yoshimi, Kenji, Mochizuki, Hideki, Yamazaki, Kazuto, Ogawa, Satoshi, Fukuda, Keiichi
• Format: Article
• Language: English
• Subjects: Adrenergic Fibers - physiology; Animals; Biological and medical sciences; Dopamine - metabolism; Endothelin-1 - metabolism; Fundamental and applied biological sciences. Psychology; GAP-43 Protein - metabolism; Gene Expression Regulation; Heart Failure - physiopathology; Heart Ventricles - innervation; Heart Ventricles - physiopathology; Hypertension, Pulmonary - complications; Hypertrophy, Right Ventricular - etiology; Hypertrophy, Right Ventricular - metabolism; Hypertrophy, Right Ventricular - physiopathology; Kinetics; Male; Medical sciences; Monocrotaline; Myocytes, Cardiac - metabolism; Nerve Growth Factor - genetics; Nerve Growth Factor - physiology; Neural Cell Adhesion Molecule L1 - metabolism; Norepinephrine - biosynthesis; Norepinephrine - metabolism; Pneumology; Pulmonary hypertension. Acute cor pulmonale. Pulmonary embolism. Pulmonary vascular diseases; Rats; Rats, Wistar; Sialic Acids - metabolism; Tubulin - metabolism; Tyrosine 3-Monooxygenase - metabolism; Up-Regulation; Vertebrates: cardiovascular system
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/01.RES.0000269828.62250.ab

Neuronal function and innervation density is regulated by target organ-derived neurotrophic factors. Although cardiac hypertrophy drastically alternates the expression of various growth factors such as endothelin-1, angiotensin II, and leukemia inhibitory factor, little is known about nerve growth factor expression and its effect on the cardiac sympathetic nerves. This study investigated the impact of pressure overload-induced cardiac hypertrophy on the innervation density and cellular function of cardiac sympathetic nerves, including kinetics of norepinephrine synthesis and reuptake, and neuronal gene expression. Right ventricular hypertrophy was induced by monocrotaline treatment in Wistar rats. Newly developed cardiac sympathetic nerves expressing β3-tubulin (axonal marker), GAP43 (growth-associated cone marker), and tyrosine hydroxylase were markedly increased only in the right ventricle, in parallel with nerve growth factor upregulation. However, norepinephrine and dopamine content was paradoxically attenuated, and the protein and kinase activity of tyrosine hydroxylase were markedly downregulated in the right ventricle. The reuptake of [I]-metaiodobenzylguanidine and [H]-norepinephrine were also significantly diminished in the right ventricle, indicating functional downregulation in cardiac sympathetic nerves. Interestingly, we found cardiac sympathetic nerves in hypertrophic right ventricles strongly expressed highly polysialylated neural cell adhesion molecule (PSA-NCAM) (an immature neuron marker) as well as neonatal heart. Taken together, pressure overload induced anatomical sympathetic hyperinnervation but simultaneously caused deterioration of neuronal cellular function. This phenomenon was explained by the rejuvenation of cardiac sympathetic nerves as well as the hypertrophic cardiomyocytes, which also showed the fetal form gene expression.