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.
Park
Ho-Jin
HJ
Tufts Medical Center, Molecular Cardiology Research Institute, 750 Washington St., Box 8486, Boston, MA 02111, USA. hpark@tuftsmedicalcenter.org
Zhang
Yali
Y
Du
Chuang
C
Welzig
C Michael
CM
Madias
Christopher
C
Aronovitz
Mark J
MJ
Georgescu
Serban P
SP
Naggar
Isaac
I
Wang
Bo
B
Kim
Young-Bum
YB
Blaustein
Robert O
RO
Karas
Richard H
RH
Liao
Ronglih
R
Mathews
Clayton E
CE
Galper
Jonas B
JB
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