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

作者：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

来源：Heart and Vessels, 2013, 28(5): 646-657.

DOI：10.1007/s00380-012-0311-0

• ANP
• Cardiac remodeling
• Tenascin-C
• Inflammation
• Endothelin-1

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 mu g/kg/min Ang II for 14 days. The Ang II + ANP and ANP rats also received 0.1 mu g/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 %26lt; 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 %26lt; 0.001) and average myocyte diameters greater (P %26lt; 0.01) in the Ang II rats than in controls. ANP decreased both myocardial fibrosis (P %26lt; 0.01) and myocyte hypertrophy (P %26lt; 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.

• 出版日期2013-9