Abstract 3576: Deficient Cardiac Neuregulin-ErbB Signaling in Type 2 Diabetes, and Beneficial Effects of Treatment With Neuregulin-1
Introduction The neuregulin-ErbB pathway is a paracrine cardioprotective system. Activation of this pathway by exogenous neuregulin-1 (NRG-1) improves cardiac function and prognosis of animals with ischemic, toxic, and viral cardiomyopathy. In this study, we measured the activity of the NRG-1-ErbB system in the left ventricle (LV) of type 2 diabetic mice, and analyzed the effects of chronic NRG-1 treatment on cardiac muscle performance and vascular reactivity. Insulin treatment was used for comparison.
Methods We used a mouse model of type 2 diabetes (db/db mice) with obesity and hyperglycemia (age 9 –30 weeks, n=25) and control db/+ mice (n=12). From the age of 9 weeks, diabetic mice were treated with NRG-1 (i.p., 10 μg/kg/day during 10 weeks, n=7) or insulin (s.c., n=6, with partial correction of hyperglycemia from 548±32 to 464±40 mg/dl, p>0.05). Protein expression of NRG-1, of ErbB2 and ErbB4 receptors, and of tyrosine phosphorylated ErbB2 and ErbB4 in the LV were analyzed by Western blotting. Cardiac muscle performance and aortic ring reactivity were analyzed in vitro.
In diabetes mice, LV levels of phosphorylated ErbB2 and ErbB4 were markedly depressed (decrease by 52±8% and 61±6%, p<0.01 vs. db/+, age and sex-independent), whereas total levels of these receptors remained unchanged. By contrast, LV expression of NRG-1 was increased (+59±7%, p<0.001 vs. db/+, n=4 –5), indicating deficient ErbB receptor activation.
Mechanical performance of isolated cardiac muscle of diabetic mice was disturbed: isometric twitches were significantly prolonged with a markedly delayed onset of isometric relaxation (after 93±2 vs. 78±3 ms in db/+ mice, p<0.05 vs. db/+ mice). Baseline active isometric tension and inotropic responses to isoproterenol (10 –9 –10 – 4 M) were identical in all groups.
In aortic rings, endothelium-dependent vasorelaxation was impaired in diabetic vs. control mice (p<0.05, two-way ANOVA, n=7– 8), and remained impaired in NRG-1- and insulin-treated animals.
Conclusion Type 2 diabetes in mice leads to deficient ErbB receptor activation in the LV and to delayed cardiac muscle relaxation. Chronic treatment with NRG-1, but not with insulin, reversed these cardiac muscle disturbances, but did not affect impaired vascular reactivity.