Cilostazol Attenuates AngII-Induced Cardiac Fibrosis in apoE Deficient Mice

• Published in: International journal of molecular sciences 2022-08, Vol.23 (16), p.9065
• Main Authors: Hada, Yoshiko, Uchida, Haruhito A, Umebayashi, Ryoko, Yoshida, Masashi, Wada, Jun
• Format: Article
• Language: English
• Subjects: Angiotensin; Angiotensin II; Angiotensin II - metabolism; Animals; Apolipoprotein E; Attenuation; Blood platelets; Blood pressure; Body weight; cAMP-PKA; Cardiomyocytes; cilostazol; Cilostazol - pharmacology; Collagen; Extracellular matrix; Fibrosis; Forskolin; Gene expression; Growth factors; Heart; Heart failure; Humans; Inflammation; Ischemia; Male; Mice; Mice, Inbred C57BL; Mice, Knockout, ApoE; Mortality; Myocardium; Myocardium - pathology; Myocytes; Osteopontin; Phosphodiesterase; Protein kinase A; Proteins; RNA, Messenger; Signs and symptoms; Vascular diseases
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms23169065

Cardiac fibrosis is characterized by the net accumulation of extracellular matrix in the myocardium and is an integral component of most pathological cardiac conditions. Cilostazol, a selective inhibitor of phosphodiesterase type III with anti-platelet, anti-mitogenic, and vasodilating properties, is widely used to treat the ischemic symptoms of peripheral vascular disease. Here, we investigated whether cilostazol has a protective effect against Angiotensin II (AngII)-induced cardiac fibrosis. Male apolipoprotein E-deficient mice were fed either a normal diet or a diet containing cilostazol (0.1% wt/wt). After 1 week of diet consumption, the mice were infused with saline or AngII (1000 ng kg−1 min−1) for 28 days. AngII infusion increased heart/body weight ratio (p < 0.05), perivascular fibrosis (p < 0.05), and interstitial cardiac fibrosis (p < 0.0001), but were significantly attenuated by cilostazol treatment (p < 0.05, respectively). Cilostazol also reduced AngII-induced increases in fibrotic and inflammatory gene expression (p < 0.05, respectively). Furthermore, cilostazol attenuated both protein and mRNA abundance of osteopontin induced by AngII in vivo. In cultured human cardiac myocytes, cilostazol reduced mRNA expression of AngII-induced osteopontin in dose-dependent manner. This reduction was mimicked by forskolin treatment but was cancelled by co-treatment of H-89. Cilostazol attenuates AngII-induced cardiac fibrosis in mice through activation of the cAMP−PKA pathway.