Published online before print May 7, 2009, doi: 10.1161/CIRCRESAHA.109.193995
© 2009 American Heart Association, Inc.
Integrative Physiology |
Role of SREBP-1 in the Development of Parasympathetic Dysfunction in the Hearts of Type 1 Diabetic Akita Mice
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., R.H.K., J.B.G.), 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.
Correspondence to Jonas Bernard Galper, Tufts Medical Center, Molecular Cardiology Research Institute, 750 Washington St., Box 8486, Boston, MA 02111. E-mail jgalper{at}tuftsmedicalcenter.org, or Ho-Jin Park hpark@tuftsmedicalcenter.org
Rationale: Diabetic autonomic neuropathy (DAN), 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-1 (SREBP-1) is a lipid-sensitive transcription factor.
Objective: We describe a unique SREBP-1–dependent mechanism for insulin regulation of cardiac parasympathetic response in a mouse model for DAN.
Methods and Results: Using implantable EKG transmitters, we demonstrated that compared with wild-type, Ins2Akita type I diabetic mice demonstrated a decrease in the negative chronotropic response to carbamylcholine characterized by a 2.4-fold decrease in the 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). Whole-cell patch-clamp studies of atrial myocytes from Akita mice exhibited a markedly decreased carbamylcholine stimulation of IKAch with a peak value of –181±31 pA/pF compared with –451±62 pA/pF (P<0.01) in cells from wild-type mice. Western blot analysis of extracts of Akita mice demonstrated that insulin treatment 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), which was reversed by overexpression of dominant negative SREBP-1. Finally, adenoviral expression of SREBP-1 in Akita atrial myocytes reversed the impaired IKAch to levels in cells from wild-type mice.
Conclusions: 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 DAN in response to insulin deficiency in the diabetic heart.
Key Words: diabetic autonomic neuropathy • SREBP • insulin deficiency • GIRK channel