Role of SREBP-1 in the development of parasympathetic dysfunction in the hearts of type 1 diabetic Akita mice.
BACKGROUND
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, I(KAch), 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.


RESULTS
Using implantable EKG transmitters, we demonstrated that compared with wild-type, Ins2(Akita) 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 I(KAch) 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 I(KAch) 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 I(KAch) 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.
Tufts Medical Center, Molecular Cardiology Research Institute, 750 Washington St., Box 8486, Boston, MA 02111, USA. hpark@tuftsmedicalcenter.org
Ho-Jin
HJ
Park
Yali
Y
Zhang
Chuang
C
Du
C Michael
CM
Welzig
Christopher
C
Madias
Mark J
MJ
Aronovitz
Serban P
SP
Georgescu
Isaac
I
Naggar
Bo
B
Wang
Young-Bum
YB
Kim
Robert O
RO
Blaustein
Richard H
RH
Karas
Ronglih
R
Liao
Clayton E
CE
Mathews
Jonas B
JB
Galper
D000818:Animals; D002217:Carbachol / Q000494:pharmacology; D002478:Cells, Cultured; D002642:Chick Embryo; D018678:Cholinergic Agents / Q000494:pharmacology; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism* / Q000473:pathology; D003929:Diabetic Neuropathies / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000235:genetics / Q000378:metabolism; D006321:Heart / Q000294:innervation*; D006325:Heart Atria / Q000378:metabolism / Q000473:pathology; D006352:Heart Ventricles / Q000378:metabolism / Q000473:pathology; D007328:Insulin / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010275:Parasympathetic Nervous System / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D018408:Patch-Clamp Techniques; D011384:Proinsulin / Q000378:metabolism; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism*
D018678:Cholinergic Agents; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D007328:Insulin; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D002217:Carbachol; D011384:Proinsulin