Role of SREBP-1 in the Development of Parasympathetic Dysfunction in the Hearts of Type 1 Diabetic Akita Mice

Abstract

Key Words: diabetic autonomic neuropathy Ⅲ SREBP Ⅲ insulin deficiency Ⅲ GIRK channel D iabetes mellitus is associated with severe debilitating complications that include a diabetic autonomic neuropathy (DAN) characterized by impairment of vascular reflexes, occasional hypotension, and decreased sympathetic and parasympathetic responsiveness of the heart. 1 Approximately 50% of patients with diabetes for 10 years or more demonstrate an impaired response of the heart to parasympathetic stimulation. 2 The presence of DAN is a significant risk factor, as demonstrated by a 5-fold higher 5-year mortality compared with diabetics without DAN. 3 Parasympathetic regulation of the heart has both a neuronal component involving vagal stimulation of parasympathetic ganglia in the atria and atrioventricular node, followed by release of acetylcholine, and a molecular component involving an intrinsic cardiac signaling pathway that mediates the parasympathetic response to acetylcholine. The latter involves the binding of acetylcholine to M 2 muscarinic receptors on the surface of cardiomyocytes and dissociation of the heterotrimeric G protein G i2 into G␣ i2 and G␤␥ subunits. G␤␥ binds to and activates the G protein-coupled inward rectifying K ϩ channel (GIRK1) 2 /(GIRK4) 2 , the channel that is responsible for I KAch (acetylcholine-gated K ϩ current), resulting in a decrease in the rate of diastolic depolarization and a decrease in heart rate (negative chronotropic effect). 4,5

Increased inducibility of ventricular tachycardia and decreased heart rate variability in a mouse model for type 1 diabetes: effect of pravastatin

“…Although the in vivo experiments shown in Fig. 3 demonstrated the inducibility of VT in the Akita mouse heart, we (23) had previously demonstrated parasympathetic dysfunction in these mice. Given that denervated Langendorfperfused hearts lacked autonomic input, we determined whether excess unopposed sympathetic stimulation might predispose these hearts to the inducibility of VT. We compared the effect of perfusion of hearts with a solution 0.1 M isoproterenol on the inducibility of VT in hearts from WT and Akita mice.…”

“…The Akita mice used in this study demonstrated marked hyperglycemia (500 Ϯ 28 mg/dl), and body weight was significantly lower in Akita mice compared with wild-type (WT) mice (Table 1). We (23) have previously demonstrated that there are no significant differences in electrolytes, acid-base balance, or left ventricular function between WT and Akita mice. In the present study, six protocols were undertaken.…”

“…Interestingly, pravastatin treatment of Akita mice also significantly increased the HF fraction compared with placebo treatment and significantly increased the HR response to atropine treatment, suggesting that the reversal of the parasympathetic dysfunction in the diabetic heart in response to pravastatin might play a role in the decreased inducibility of VT. Although HRV reflects the response of the heart to autonomic input from the central nervous system via vagal and sympathetic nerves, the role of autonomic imbalance in the inducibility of VT in the Akita mouse was further supported by the finding that treatment of the Akita mouse with carbamylcholine, which directly activates the parasympathetic response at the level of the M 2 muscarinic receptor in the heart muscle, thus bypassing vagal innervation (23), protected the heart from the inducibility of VT. Furthermore, ␤-adrenergic blockade of sympathetic input to the heart by propranolol also attenuated the inducibility of VT in the Akita mouse.…”

“…The heterozygous Akita mice used in this study survive for up to a year and develop secondary effects of diabetes. We (23) have previously demonstrated that Akita mice exhibit marked parasympathetic dysfunction as determined by a blunting of the negative chronotropic response to the acetylcholine analog carbamylcholine. However, unlike HRV, the clinical significance of a decreased HR response to parasympathetic stimulation is less well established.…”

Complexity of Impaired Parasympathetic Heart Rate Regulation in Diabetes

“…In these animals, a point mutation in the insulin 2 gene leads to production of a misfolded protein, pancreatic b-cell destruction, and a metabolic phenotype resembling type 1 diabetes. In an earlier study, the authors had observed diminished bradycardia to muscarinic cholinergic stimulation with carbamylcholine in diabetic Akita mice (10). In this model, impaired parasympathetic heart rate control may result in part from reduced cardiac responsiveness to the parasympathetic neurotransmitter acetylcholine.…”