Impaired coronary microvascular dilation correlates with enhanced vascular smooth muscle MLC phosphorylation in diabetes.
OBJECTIVE
Impaired endothelium-independent vasodilation is a known consequence of types 1 and 2 diabetes, and the mechanism of impaired vasodilation is not well understood. The following study investigated the effects of types 1 and 2 diabetes in endothelial-independent vasodilation associated with coronary vascular smooth muscle (VSM) relaxation and contractile signaling mechanisms.


METHODS
Type 1 diabetes was induced in Yucatan miniswine via alloxan injection and treated with or without insulin (DM and IDM). Nondiabetic swine served as controls (ND). Expression and/or phosphorylation of determinants of VSM relaxation and contraction signaling were examined in coronary arteries and microvessels. Coronary microvessel relaxation was assessed by using sodium nitroprusside (SNP). In addition, SNP-induced vasodilation and myosin light-chain (MLC) phosphorylation was determined in coronary microvessels isolated from ND and type 2 diabetic human atrial appendage.


RESULTS
Diabetic impairment in SNP-induced relaxation was completely normalized by insulin. Soluble guanylate cyclase (sGC) VSM expression decreased in both DM and IDM groups and did not correlate with vasorelaxation. Phosphorylation of MLC and myosin phosphatase increased in the DM group and MLC phosphorylation strongly correlated with impaired VSM relaxation (r=0.670, P<0.01). Coronary microvessels from type 2 diabetic human patients exhibited similarly impaired vasodilation and enhanced VSM MLC phosphorylation.


CONCLUSIONS
Impaired vasodilation in type 1 diabetes correlates with enhanced VSM MLC phosphorylation. In addition, enhanced VSM MLC phosphorylation is associated with impaired vasodilation in type 2 diabetes in humans.
Clements
Richard T
RT
Cardiothoracic Research Lab, Department of Surgery, Beth Israel Deaconess Medical Center and Harvard Medical School, 110 Francis Street, Boston, MA 02215, USA.
Sodha
Neel R
NR
Feng
Jun
J
Boodhwani
Munir
M
Liu
Yuhong
Y
Mieno
Shigetoshi
S
Khabbaz
Kamal R
KR
Bianchi
Cesario
C
Sellke
Frank W
FW
D000496:Alloxan / Q000633:toxicity; D000818:Animals; D003331:Coronary Vessels / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000494:pharmacology; D055806:Microvessels / Q000378:metabolism; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D018994:Myosin Light Chains / Q000378:metabolism*; D043263:Myosin-Light-Chain Phosphatase / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D013552:Swine; D013556:Swine, Miniature; D014664:Vasodilation / Q000187:drug effects
D007004:Hypoglycemic Agents; D007328:Insulin; D018994:Myosin Light Chains; D000496:Alloxan; D043263:Myosin-Light-Chain Phosphatase