Enhanced negative modulation of urotensin II on cardiac function and [Ca2+]i regulation in a diabetic rat model: Insights into molecular and cellular mechanisms

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 392; no. 6; p. 103594
• Main Authors: Zhang, Xiaowei, Chen, Zhe, Cao, Jing, Zhou, Peng, Zhang, Zhi, Sun, Xiaoqiang, Liu, Yixi, Li, Tiankai, Cheng, Heng-Jie, Cheng, Che Ping
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 01.06.2025
• Subjects: Animals; Calcium - metabolism; Calcium handling; Cardiomyocytes; Contractility; Diabetes mellitus; Diabetes Mellitus, Experimental - metabolism; Diabetes Mellitus, Experimental - physiopathology; Male; Myocardial Contraction - drug effects; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - metabolism; Rats; Rats, Sprague-Dawley; Receptors, G-Protein-Coupled - metabolism; Urotensin II; Urotensins - metabolism; Urotensins - pharmacology; ICa,L; τ; VES; DM; EES/EA; LV; SA; dV/dtmax; P; PTX; V; dL/dtmax; STZ; Urotensin II; EA; UT; EF; SV; SW; Diabetes mellitus; Contractility; Cardiomyocytes; dR/dtmax; PED; DCM; MSW; EES; UII; VED; Db-cAMP; Calcium handling; [Ca2+]iT; HF; PES
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1016/j.jpet.2025.103594

The direct cardiac effects of urotensin II (UII) in normal and diabetic subjects remain controversial. The alteration and functional significance of cardiac UII/UII receptor (UT) in diabetes are still unclear. We assessed the hypothesis that in diabetes, the cardiomyocyte UII/UT system is increased. This augmentation is proposed to exacerbate the dysfunctional [Ca2+]i regulation, enhance inhibitions of left ventricle (LV) and myocyte contraction and relaxation, leading to worsening cardiac dysfunction. We compared LV myocyte UII and UT expression, LV and myocyte contractile, [Ca2+]i transient ([Ca2+]iT) and calcium current (ICa,L) responses to UII stimulation in male Sprague–Dawley rats (12/group) with streptozotocin-induced diabetes mellitus and controls. We found that UII and UT protein levels were significantly greater in diabetic myocytes than in control myocytes. Compared with control rats, UII (400 pmol/kg, i.p.) administration produced greater decreases in LV contractility of EES (diabetes mellitus: 32% vs C: 13%) and MSW with significantly increased LV time constant relaxation in diabetes. In response to UII (10–5 M) superfusion, diabetic myocytes had much greater decreases in the velocity of shortening and relengthening accompanied by significantly larger decreases in the peak systolic [Ca2+]iT and ICa,L (29% vs 15%). These responses were abolished by pretreatment of diabetic myocytes with urantide, pertussis toxin, or dibutyryl-cAMP, respectively. We conclude that UII has direct negative inotropic and lusitropic cardiac effects in both normal and diabetic rats. In diabetes, cardiac UII/UT is upregulated, enhancing UII-caused negative modulation on cardiac function and [Ca2+]i regulation. This may contribute to the progression of cardiac dysfunction in diabetes and diabetic cardiomyopathy. Urotensin II (UII) has direct negative inotropic and lusitropic cardiac effects in both normal and diabetic rats. Compared with normal rats, cardiac UII/UII receptors (UT) were upregulated in diabetic rats, resulting in significantly greater decreases in [Ca2+]iT and ICa,L and increased inhibitions of left ventricle and myocyte contraction and relaxation. These effects are coupled with UT and mediated by Gi proteins. These data provide new insights and evidence that upregulation of cardiomyocyte UII/UT may promote the progressive cardiac dysfunction in diabetes and diabetic cardiomyopathy.