Abstract 9259: Upregulation of Cardiac Urotensin II (UII) Exacerbates UII Stimulation-Induced Negative Modulation on Myocyte Contractile Function and Ca2+ Current in Streptozotocin-Induced Diabetic Rats
Background. Urotensin II (U-II), a somatostatin-like peptide is a potent vasoconstrictor. It has been implicated in metabolic regulation. In diabetes mellitus (DM) patients, circulating UII levels are increased. Recent evidence suggests that UII plays a significant role in DM and its complications, such as diabetic cardiomyopathy. However, the mechanisms are unclear. Whether UII alters cardiac contractile behavior in DM is unknown. We tested the hypothesis that DM causes upregulation of myocyte UII and its receptors (UT). This may exacerbate UII stimulation-induced negative modulation on myocyte function and Ca2+ current and contribute to the progression of left ventricular (LV) dysfunction in DM.
Methods. We compared LV myocyte UII and UT expression, myocyte contractile, and L-type Ca2+ current (ICa,L) responses to UII stimulation in 8 rats at 6 weeks after receiving streptozotocin (STZ, 35 mg/kg, ip) and 8 age-matched normal control (C) rats.
Results. Compared with controls, STZ-treated rats (DM rats) had more than 4-fold elevated blood glucose levels (DM: 569 vs C: 108 mg/dl) and reduced body weight followed by cardiomyocyte systolic and diastolic dysfunction with significant decreases in the peak velocity of myocyte shortening (dL/dtmax) (28%, DM: 88.4 ± 5.2 vs C:122.7 ± 4.8 μm/s), relengthening (dR/dtmax) (21%, -73.1 ± 4.9 vs -92.9 ± 6.0 μm/s), and ICa,L (23%, 6.1 ± 0.2 vs 7.9 ± 0.3 pA/pF). Compared to normal myocytes, in DM myocytes, both UII (26%, DM: 0.58 vs C: 0.46) and UT (20%, 0.91 vs 0.76) mRNA and protein levels were significantly increased. Importantly, these changes were associated with enhanced UII-mediated negative modulation on myocyte contraction, relaxation, and ICa,L. Compared to normal myocytes, in DM myocytes, superfusion UII (10-5 M) caused significantly greater decreases in dL/dtmax (DM: 24% vs C:11%) and dR/dtmax (28% vs 14%) accompanied by significantly larger reductions in ICa,L (19% vs 9.8%) (P<0.01).
Conclusions. STZ-induced DM causes upregulation of cardiac UII system, which enhances inhibition of cardiomyocyte contraction, relaxation, and ICa,L and, thus, may play an important role in the development and progression of diabetic cardiomyopathy.
- © 2011 by American Heart Association, Inc.