Atrial natriuretic peptide exerts protective action against angiotensin II-induced cardiac remodeling by attenuating inflammation via endothelin-1/endothelin receptor A cascade

• Published in: Heart and vessels 2013-09, Vol.28 (5), p.646-657
• Main Authors: Fujita, Shuichi, Shimojo, Naoshi, Terasaki, Fumio, Otsuka, Kaoru, Hosotani, Noriko, Kohda, Yuka, Tanaka, Takao, Nishioka, Tomohiro, Yoshida, Toshimichi, Hiroe, Michiaki, Kitaura, Yasushi, Ishizaka, Nobukazu, Imanaka-Yoshida, Kyoko
• Format: Article
• Language: English
• Subjects: Angiotensin II; Animals; Anti-Inflammatory Agents - administration & dosage; Anti-Inflammatory Agents - pharmacology; Atrial Natriuretic Factor - administration & dosage; Atrial Natriuretic Factor - pharmacology; Biomedical Engineering and Bioengineering; Cardiac Surgery; Cardiology; Cardiomegaly - metabolism; Cardiomegaly - pathology; Cardiomegaly - prevention & control; Cardiovascular system; Cells, Cultured; Disease Models, Animal; Endothelin-1 - metabolism; Fibrillar Collagens - metabolism; Fibroblasts - drug effects; Fibroblasts - metabolism; Fibrosis; Heart Diseases - chemically induced; Heart Diseases - metabolism; Heart Diseases - pathology; Heart Diseases - physiopathology; Heart Diseases - prevention & control; Inflammation - chemically induced; Inflammation - metabolism; Inflammation - pathology; Inflammation - physiopathology; Inflammation - prevention & control; Inflammation Mediators - metabolism; Infusions, Intravenous; Macrophages - drug effects; Macrophages - metabolism; Male; Medicine; Medicine & Public Health; Mitral Valve - drug effects; Mitral Valve - physiopathology; Myocardial Contraction - drug effects; Myocardium - metabolism; Myocardium - pathology; Original Article; Peptides; Rats; Rats, Inbred WKY; Receptor, Endothelin A - metabolism; Rodents; Signal Transduction - drug effects; Stroke Volume - drug effects; Time Factors; Vascular Surgery; Ventricular Function, Left - drug effects; Ventricular Remodeling - drug effects
• ISSN: 0910-8327; 1615-2573
• DOI: 10.1007/s00380-012-0311-0

We aimed to investigate whether atrial natriuretic peptide (ANP) attenuates angiotensin II (Ang II)-induced myocardial remodeling and to clarify the possible molecular mechanisms involved. Thirty-five 8-week-old male Wistar–Kyoto rats were divided into control, Ang II, Ang II + ANP, and ANP groups. The Ang II and Ang II + ANP rats received 1 μg/kg/min Ang II for 14 days. The Ang II + ANP and ANP rats also received 0.1 μg/kg/min ANP intravenously. The Ang II and Ang II + ANP rats showed comparable blood pressure. Left ventricular fractional shortening and ejection fraction were lower in the Ang II rats than in controls; these indices were higher ( P < 0.001) in the Ang II + ANP rats than in the Ang II rats. In the Ang II rats, the peak velocity of mitral early inflow and its ratio to atrial contraction-related peak flow velocity were lower, and the deceleration time of mitral early inflow was significantly prolonged; these changes were decreased by ANP. Percent fibrosis was higher ( P < 0.001) and average myocyte diameters greater ( P < 0.01) in the Ang II rats than in controls. ANP decreased both myocardial fibrosis ( P < 0.01) and myocyte hypertrophy ( P < 0.01). Macrophage infiltration, expression of mRNA levels of collagen types I and III, monocyte chemotactic protein-1, and a profibrotic/proinflammatory molecule, tenascin-C (TN-C) were increased in the Ang II rats; ANP significantly decreased these changes. In vitro, Ang II increased expression of TN-C and endothelin-1 (ET-1) in cardiac fibroblasts, which were reduced by ANP. ET-1 upregulated TN-C expression via endothelin type A receptor. These results suggest that ANP may protect the heart from Ang II-induced remodeling by attenuating inflammation, at least partly through endothelin 1/endothelin receptor A cascade.