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Signaling of soluble guanylate cyclase (sGC) has protective effect on cardiovascular disease and chemosensitization effect on cancer. Bay 60-2770 is a more effective activator of oxidized (heme-free) sGC and acts independent on nitric oxide. We aimed to investigate the role of sGC on doxorubicin (Dox)-induced dilated cardiomyopathy.
9-week-old male Sprague Dawley rats were administrated 3.33 mg/kg Dox (total dose: 20 mg/kg) and 1 mg/kg Bay 60-2770 (total dose: 6 mg/kg) for 2 weeks, divided 6 times by intraperitoneal injection and gavage respectively. Four weeks after first Dox administration, echocardiography and hemodynamic values were analyzed. For in vitro study, H9C2 cardiomyocytes were treated with 10 μM Bay 60-2770 24hr prior to Dox (0.5-10 μM). To understand the role for regulating of apoptosis, Bcl-2, Bax and cleaved caspase3 levels were detected by western blotting. In addition, the changes of sGCα1, sGCβ1 and PKG1 expression level under Dox and Bay 60-2770 exposure also examined.
The results of echocardiographic studies indicate that Bay 60-2770 preserved left ventricular function compared with Dox treated, left ventricular end diastolic volume (LVEDV): (Dox 0.671 ± 0.234 vs. Bay 0.549 ± 0.091), left ventricular end systolic volume (LVESV): (Dox 0.125 ± 0.057 vs. Bay 0.07 ± 0.015) ,left ventricular ejection fraction (LVEF): (Dox 78.61 ± 5.916 vs. Bay 85.72 ± 2.217) , left ventricular fractional shortening (LVFS): (Dox 39.46 ± 7.759 vs. Bay 41.36 ± 2,241). In cardiomyocytes, Dox-induced caspase-3 activation was decreased with 24 hr pretreatment of 10 μM Bay 60-2770, which accompanied with VASP activation by Bay 60-2770. In Dox rats, Bay 60-2770 treatment show increased ratio of sGCβ1/α1 significantly but not sGCβ1 or sGCα1, and the increased ratio of sGCβ1/α1 accompanied with PKG1 activation. Though the level of sGCβ1 increased significantly, there’s no sGC-PKG1 signal activation.
The new sGC activator, Bay 60-2770 ameliorated Dox-induced cardiomyopathy, regulating the ratio of sGCβ1/α1, but not expression level. We investigated the novel role of sGC as a therapeutic target against Dox-induced dilated cardiomyopathy.