Zhang Xiaowei, Chen Zhe, Cao Jing, Zhou Peng, Zhang Zhi, Sun Xiaoqiang, Liu Yixi, Li Tiankai, Cheng Heng-Jie, Cheng Che Ping
Department of Cardiology, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China; Department of Cardiovascular Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina.
Department of Cardiovascular Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina; Department of Endocrinology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China.
J Pharmacol Exp Ther. 2025 Jun;392(6):103594. doi: 10.1016/j.jpet.2025.103594. Epub 2025 Apr 29.
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 [Ca] 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, [Ca] transient ([Ca]) and calcium current (I) 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 E (diabetes mellitus: 32% vs C: 13%) and M with significantly increased LV time constant relaxation in diabetes. In response to UII (10 M) superfusion, diabetic myocytes had much greater decreases in the velocity of shortening and relengthening accompanied by significantly larger decreases in the peak systolic [Ca] and I (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 [Ca] regulation. This may contribute to the progression of cardiac dysfunction in diabetes and diabetic cardiomyopathy. SIGNIFICANCE STATEMENT: 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 [Ca] and I and increased inhibitions of left ventricle and myocyte contraction and relaxation. These effects are coupled with UT and mediated by G 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.
尾加压素II（UII）对正常和糖尿病患者心脏的直接作用仍存在争议。糖尿病患者心脏中UII/UII受体（UT）的变化及其功能意义尚不清楚。我们评估了以下假设：在糖尿病患者中，心肌细胞UII/UT系统会增加。这种增加被认为会加剧功能失调的[Ca]调节，增强对左心室（LV）和心肌细胞收缩与舒张的抑制作用，从而导致心脏功能障碍恶化。我们比较了链脲佐菌素诱导的糖尿病雄性Sprague-Dawley大鼠（每组12只）和对照组大鼠左心室心肌细胞中UII和UT的表达、左心室和心肌细胞的收缩性、[Ca]瞬变（[Ca]）以及对UII刺激的钙电流（I）反应。我们发现，糖尿病心肌细胞中UII和UT蛋白水平显著高于对照心肌细胞。与对照大鼠相比，腹腔注射UII（400 pmol/kg）后，糖尿病大鼠左心室收缩性E（糖尿病：32% vs 对照：13%）和M的下降幅度更大，且糖尿病大鼠左心室时间常数舒张显著增加。对UII（10 μM）灌流的反应中，糖尿病心肌细胞缩短和再延长速度的下降幅度更大，同时收缩期峰值[Ca]和I的下降幅度也显著更大（29% vs 15%）。分别用尿抑胃素、百日咳毒素或二丁酰环磷腺苷预处理糖尿病心肌细胞可消除这些反应。我们得出结论，UII对正常和糖尿病大鼠心脏均有直接的负性变力性和变时性作用。在糖尿病患者中，心脏UII/UT上调，增强了UII对心脏功能和[Ca]调节的负性调节作用。这可能有助于糖尿病和糖尿病性心肌病患者心脏功能障碍的进展。意义声明：尾加压素II（UII）对正常和糖尿病大鼠心脏均有直接的负性变力性和变时性作用。与正常大鼠相比，糖尿病大鼠心脏UII/UII受体（UT）上调，导致[Ca]和I的下降幅度显著更大，对左心室和心肌细胞收缩与舒张的抑制作用增强。这些作用与UT相关并由G蛋白介导。这些数据为心肌细胞UII/UT上调可能促进糖尿病和糖尿病性心肌病患者进行性心脏功能障碍提供了新的见解和证据。
