title: Atrial natriuretic peptide exerts protective action against angiotensin II-induced cardiac remodeling by attenuating inflammation via endothelin-1/endothelin receptor A cascade.
abstract: 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.
authors.affiliation: Department of Cardiology, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki, Osaka, 569-8686, Japan.
authors.forename: Shuichi
authors.initials: S
authors.lastname: Fujita
authors.forename: Naoshi
authors.initials: N
authors.lastname: Shimojo
authors.forename: Fumio
authors.initials: F
authors.lastname: Terasaki
authors.forename: Kaoru
authors.initials: K
authors.lastname: Otsuka
authors.forename: Noriko
authors.initials: N
authors.lastname: Hosotani
authors.forename: Yuka
authors.initials: Y
authors.lastname: Kohda
authors.forename: Takao
authors.initials: T
authors.lastname: Tanaka
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Nishioka
authors.forename: Toshimichi
authors.initials: T
authors.lastname: Yoshida
authors.forename: Michiaki
authors.initials: M
authors.lastname: Hiroe
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Kitaura
authors.forename: Nobukazu
authors.initials: N
authors.lastname: Ishizaka
authors.forename: Kyoko
authors.initials: K
authors.lastname: Imanaka-Yoshida
mesh_terms: D000804:Angiotensin II; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000494:pharmacology*; D009320:Atrial Natriuretic Factor / Q000008:administration & dosage / Q000494:pharmacology*; D006332:Cardiomegaly / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D002478:Cells, Cultured; D004195:Disease Models, Animal; D019332:Endothelin-1 / Q000378:metabolism*; D024022:Fibrillar Collagens / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D005355:Fibrosis; D006331:Heart Diseases / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D018836:Inflammation Mediators / Q000378:metabolism; D007262:Infusions, Intravenous; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008943:Mitral Valve / Q000187:drug effects / Q000503:physiopathology; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D011921:Rats, Inbred WKY; D044022:Receptor, Endothelin A / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D013318:Stroke Volume / Q000187:drug effects; D013997:Time Factors; D016277:Ventricular Function, Left / Q000187:drug effects; D020257:Ventricular Remodeling / Q000187:drug effects*
chemical_list: D000893:Anti-Inflammatory Agents; D019332:Endothelin-1; D024022:Fibrillar Collagens; D018836:Inflammation Mediators; D044022:Receptor, Endothelin A; D000804:Angiotensin II; D009320:Atrial Natriuretic Factor