Published online before print May 7, 2009, doi: 10.1161/CIRCRESAHA.109.193995
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Submitted on January 10, 2009
Revised on April 27, 2009
Accepted on April 28, 2009
Role of SREBP-1 in the Development of Parasympathetic Dysfunction in the Hearts of Type 1 Diabetic Akita Mice
Ho-Jin Park ;
From the Molecular Cardiology Research Institute (H.-J.P., Y.Z., C.M., M.J.A., S.P.G., I.N., R.O.B., R.H.K., J.B.G.) and Cardiology Division (C.M.), Department of Medicine, Tufts Medical Center; and Center for Neuroscience Research (C.D.), Department of Neuroscience, Tufts University School of Medicine, Boston, Mass; Department of Neurosciences (C.M.W.), Medical University of South Carolina, Charleston; Department of Medicine (B.W., R.L.), Brigham and Women's Hospital, Boston, Mass; Division of Endocrinology, Diabetes and Metabolism (Y.-B.K.), Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Mass; and Departments of Pathology and Immunology (C.E.M.), University of Florida College of Medicine, Gainesville.
* To whom correspondence should be addressed. E-mail: jgalper{at}tuftsmedicalcenter.org.
Diabetic autonomic neuropathy, a major complication of diabetes mellitus, is characterized in part by impaired cardiac parasympathetic responsiveness. Parasympathetic stimulation of the heart involves activation of an acetylcholine-gated K+ current, IKAch, via a (GIRK1)2/(GIRK4)2 K+ channel. Sterol regulatory element binding protein (SREBP)-1 is a lipid-sensitive transcription factor. We describe a unique SREBP-1–dependent mechanism for insulin regulation of cardiac parasympathetic response in a mouse model for diabetic autonomic neuropathy. Compared to wild-type mice, Ins2Akita type 1 diabetic mice demonstrated a decrease in the negative chronotropic response to carbamylcholine characterized by a 2.4-fold decrease in duration of bradycardia; a 52±8% decrease in atrial expression of GIRK1 (P<0.01) and a 31.3±2.1% decrease in SREBP-1 (P<0.05). Myocytes from atria of Akita mice exhibited a markedly decreased carbamylcholine stimulation of IKAch with a peak value of -181±31 pA/pF compared to 451±62 pA/pF (P<0.01) for cells from wild-type mice. Insulin treatment of Akita mice reversed the impairment in parasympathetic response and increased the expression of GIRK1, SREBP-1, and IKAch activity in atrial myocytes from these mice to levels in wild-type mice. Insulin treatment of cultured atrial myocytes stimulated GIRK1 expression 2.68±0.12-fold (P<0.01), whereas overexpression of dominant negative SREBP-1 reversed this insulin effect. Finally, adenoviral expression of SREBP-1 in Akita atrial myocytes reversed the impaired IKAch to levels in cells from wild-type. These results support a unique molecular mechanism for insulin regulation of GIRK1 expression and parasympathetic response via SREBP-1, which might play a role in the pathogenesis of diabetic autonomic neuropathy in response to insulin deficiency in the diabetic heart.
Key words: diabetic autonomic neuropathy • SREBP • insulin deficiency • GIRK channel