alpha2-Heremans Schmid glycoprotein, a putative inhibitor of tyrosine kinase, prevents glucose toxicity associated with cardiomyocyte dysfunction.
BACKGROUND
Diabetes leads to impaired glucose metabolism and insulin signaling in the heart, which may contribute to the development of diabetic cardiomyopathy. Insulin stimulates tyrosine phosphorylation of the insulin receptor and insulin receptor substrates. A two-fold increase in insulin-stimulated tyrosine phosphorylation has been reported in diabetic myocardium. The aim of the present study was to examine the effect of a putative inhibitor of tyrosine kinase phosphorylation, alpha(2)-Heremans Schmid glycoprotein (AHSG), on the mechanical dysfunction under a simulated diabetic environment.


METHODS
Isolated ventricular myocytes from adult rats were maintained for 24 h in either normal glucose (NG, 5.5 mM) or high glucose (HG, 25.5 mM) medium with 10(-7) M insulin, and in the absence or presence of AHSG (50 micro g/ml). Contractile indices analyzed included: peak shortening (PS), time-to-PS (TPS), time-to-90% relengthening (TR(90)) and area underneath shortening and relengthening (Area/PS).


RESULTS
Myocytes maintained in HG medium displayed reduced PS and prolonged TPS/TR(90), with enhanced area, compared to the NG myocytes. Interestingly, these HG-induced mechanical dysfunctions were abolished by AHSG. Removal of insulin from the culture medium did not affect the basal myocyte mechanics, but prevented AHSG from completely protecting against the HG-induced mechanical defects (i.e. HG-induced prolongation of TR(90) and area were only partially attenuated by AHSG in the absence of insulin).


CONCLUSIONS
The present data support the notion of tyrosine phosphorylation in the pathogenesis of diabetic cardiomyopathy, and implicate the therapeutic value of tyrosine kinase phosphorylation inhibitors.
Ren
Jun
J
Department of Pharmacology, Physiology, and Therapeutics, University of North Dakota School of Medicine, Grand Forks 58203, USA. jren@medicine.nodak.edu
Davidoff
Amy J
AJ
D000818:Animals; D001798:Blood Proteins / Q000494:pharmacology* / Q000502:physiology*; D009202:Cardiomyopathies / Q000503:physiopathology / Q000517:prevention & control; D002478:Cells, Cultured; D003925:Diabetic Angiopathies / Q000503:physiopathology / Q000517:prevention & control; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005947:Glucose / Q000633:toxicity*; D006321:Heart / Q000187:drug effects / Q000502:physiology*; D006352:Heart Ventricles; D007328:Insulin / Q000494:pharmacology*; D008297:Male; D032342:Muscle Cells / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D009200:Myocardial Contraction / Q000187:drug effects*; D019000:Phosphotyrosine / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley; D060749:alpha-2-HS-Glycoprotein
D001798:Blood Proteins; D004791:Enzyme Inhibitors; D007328:Insulin; D060749:alpha-2-HS-Glycoprotein; D019000:Phosphotyrosine; D011505:Protein-Tyrosine Kinases; D005947:Glucose