Introduction and Objective: The large-conductance Ca2+-activated K+ (BK) channel is critical in regulation coronary circulation, with its expression tightly regulated by Sorbin and SH3 domain-containing protein 2 (Sorbs2). Sorbs2 expression is downregulated in coronary arteries, contributing to BK channelopathy and vasculopathy in diabetic animals. However, the role of Sorbs2 in BK channel function in human vessels remains unclear.Methods: Using patch-clamp, video microscopy, and immunoblotting approaches, we examined Sorbs2 expression and BK channel function in coronary arteries from atrial appendages of patients undergoing CABG surgery.Results: Coronary microvessels were dissected from 9 type 1 diabetic (T1D) patients (6 males and 3 females, 62.8±3.3 years), 20 type 2 diabetic (T2D) patients (11 males and 9 females, 66.6±1.8 years), and 27 non-diabetic controls (18 males and 9 females, 68.8±2.0 years). Cardiac systolic function was similar across the groups (LVEF: 54.0±5.6% for T1D, 50.5±3.0% for T2D, and 56.8±1.9% for controls). However, BK channel-mediated maximal coronary vasodilation was reduced in T1D (27.3±3.4%)* and T2D (54.3±5.0%)* compared to controls (74.0±4.9%). BK channel activation to Ca2+ was also impaired, with EC50 values of 2.26±0.18 μM*# (T1D), 0.89±0.07 μM* (T2D), and 0.41±0.04 μM (controls). The expression of the BK channel α-subunit, but not the β1-subunit, was downregulated by 49.8%* in T1D and 42.6%* in T2D, accompanied by a decrease in Sorbs2 expression of 87.2%*# (T1D) and 37.5%* (T2D), respectively. *: p<0.05 vs. controls. #: p<0.05 vs. T2D.Conclusion: Diminished coronary BK channel function in human diabetes is associated with down-expression of Sorbs2, with a more pronounced decline in T1D.
X. Xiong: None. X. Sun: None. B. Quam: None. B. Stanga: None. J. Stulak: None. R. Daly: Other Relationship; Neochord, Inc. Consultant; UNOS. K. Greason: None. P. Tang: None. P. Spencer: None. Q. Chai: None. Y. Cha: None. H. Lee: None. T. Lu: None.
NHLBI, HL161821
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