Intravenous Semaphorin 3A Administration Maintains Cardiac Contractility and Improves Electrical Remodeling in a Mouse Model of Isoproterenol-Induced Heart Failure

• Published in: International Heart Journal Vol. 64; no. 3; pp. 453 - 461
• Main Authors: Kurokawa, Sayaka, Kashimoto, Miwa, Hagikura, Kazuhiro, Shimodai-Yamada, Sayaka, Otsuka, Naoto, Wakamatsu, Yuji, Nagashima, Koichi, Matsumoto, Taro, Hao, Hiroyuki, Okumura, Yasuo
• Format: Journal Article
• Language: English
• Published: Japan International Heart Journal Association 31.05.2023; Japan Science and Technology Agency
• Subjects: Action potential; Ca2+-transporting ATPase; Cardiac remodeling; Congestive heart failure; Fibrosis; Heart failure; Innervation; Intravenous administration; Isoproterenol; Muscle contraction; Myocardium; Potassium channel; Potassium channels (voltage-gated); Semaphorins; Sympathetic nervous system; Systolic function; Ventricle; Western blotting; Cardiac remodeling; Sympathetic nervous system; Potassium channel; Systolic function
• ISSN: 1349-2365; 1349-3299
• DOI: 10.1536/ihj.22-705

The effects of recombinant semaphorin 3A (Sema3A) on myocardial contractility and electrical remodeling in mice with isoproterenol (ISP) -induced heart failure were investigated.C57BL/6J mice intraperitoneally received ISP (480 mg/kg/day, ISP group; n = 24) or saline (control group; n = 31) for 14 days. Twenty-one ISP-treated mice received 0.5 mg/kg Sema3A intravenously on days 7 and 11 (ISP+Sema3A group). The sympathetic nervous system was activated upon ISP treatment, but was reduced upon Sema3A administration. Greater myocardial tissue fibrosis was observed in the ISP group than in the control group. However, fibrosis was not significantly different between the ISP+Sema3A and control groups. Fractional shortening of the left ventricle was lower in the ISP group than in the control group and was restored in the ISP+Sema3A group (control, 53 ± 8%; ISP, 37 ± 7%; ISP+Sema3A, 48 ± 3%; P < 0.05). Monophasic action potential duration at 20% repolarization (MAPD20) was prolonged in the ISP group (compared to control group), but this was reversed upon Sema3A administration (control, 29 ± 3 ms; ISP, 35 ± 6 ms; ISP+Sema3A, 29 ± 3 ms; P < 0.05). qPCR revealed Kv4.3, KChIP2, and SERCA2 downregulation in the ISP group and upregulation in the ISP+Sema3A group; however, Western blotting revealed similar changes only for Kv4.3 (P < 0.05).Intravenous Sema3A may maintain myocardial contractility by suppressing the sympathetic innervation of the myocardium and reducing myocardial tissue damage, in addition to restoring MAPD via Kv4.3 upregulation.