Role of SREBP-1 in the development of parasympathetic dysfunction in the hearts of type 1 diabetic Akita mice.

Abstract

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, 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.

METHODS AND 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.

• Authors: Ho-Jin Park, Yali Zhang, Chuang Du, C Michael Welzig, Christopher Madias, Mark J Aronovitz, Serban P Georgescu, Isaac Naggar, Bo Wang, Young-Bum Kim, Robert O Blaustein, Richard H Karas, Ronglih Liao, Clayton E Mathews, Jonas B Galper
• Journal: Circulation research (Circ Res) Vol. 105 Issue 3 Pg. 287-94 (Jul 31 2009) ISSN: 1524-4571 [Electronic] United States
• PMID: 19423844 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Cholinergic Agents
• G Protein-Coupled Inwardly-Rectifying Potassium Channels
• Insulin
• Srebf1 protein, mouse
• Sterol Regulatory Element Binding Protein 1
• Carbachol
• Proinsulin

Topics

• Animals
• Carbachol (pharmacology)
• Cells, Cultured
• Chick Embryo
• Cholinergic Agents (pharmacology)
• Diabetes Mellitus, Type 1 (metabolism, pathology)
• Diabetic Neuropathies (metabolism, pathology)
• Disease Models, Animal
• G Protein-Coupled Inwardly-Rectifying Potassium Channels (genetics, metabolism)
• Heart (innervation)
• Heart Atria (metabolism, pathology)
• Heart Ventricles (metabolism, pathology)
• Insulin (metabolism, pharmacology)
• Male
• Mice
• Mice, Mutant Strains
• Myocardium (metabolism, pathology)
• Myocytes, Cardiac (drug effects, metabolism, pathology)
• Parasympathetic Nervous System (drug effects, metabolism, physiopathology)
• Patch-Clamp Techniques
• Proinsulin (metabolism)
• Sterol Regulatory Element Binding Protein 1 (genetics, metabolism)