Abstract 12920: Interaction Between Coupling Factor 6 and Ecto-F1FO Complex Induces Hypertension and Diabetes by Tissue Acidosis
Background: Protons regulate cellular function by modulating the charge and structure of macromolecules, and proton-extruding and importing transport proteins underlie pH homeostasis. The molecular rotary motor F1Fo complex, ATP synthase, was disclosed at the plasma membrane, but its ligands and functions have not been fully understood. We recently identified a circulating peptide coupling factor 6 (CF6), an endogenous prostacyclin inhibitor, as a novel ligand for F1Fo complex: After binding to protrusive F1, CF6 forces the backward rotation of Fo, resulting in proton import. We investigated the role of interaction between CF6 and ecto-F1Fo complex in the genesis of hypertension and diabetes due to tissue acidosis.
Methods and Results: We generated CF6-overexpressing transgenic mouse (TG) in which CF6 was overexpressed by two times compared with wild type mice (WT). In TG, intracellular pH measured by 31P-magnetic resonance spectroscopy was decreased by 0.1 to 0.15 pH unit in the skeletal muscle (6.96±0.03 vs 7.05±0.02, p<0.05) and the liver (7.00±0.04 vs 7.16±0.04, p<0.05) compared with WT. TG mice manifested arterial blood pressure elevation by 10 mmHg (p<0.05) under a high salt diet and diabetes under a high sucrose diet compared with WT (glucose, 133±10 vs 108±1 mg/dl; insulin, 698±87 vs 295±55 pg/ml, both p<0.05). Phospho-insulin receptor β (Tyr1150/1151) was decreased in the skeletal muscle and liver in TG compared with WT, but was similar in the adipose tissue between TG and WT. Insulin receptor substrate (IRS)-1 was decreased by 64±9% in TG compared with WT in the skeletal muscle (n=5, p<0.05), and phospho-IRS-2 (panTyr) was decreased in the TG liver. Phosphoinositide 3-kinase activity and the ratio of phospho-Akt1 (ser 473) to total Akt1 were both decreased in the skeletal muscle and liver in TG compared with WT. TG exhibited plasma membrane-bound GLUT-4 protein decrease in the skeletal muscle. Intra-peritoneal administration of amiloride, an inhibitor of proton extruder, at 50 mg/kg for 2 days exacerbated insulin resistance, while anti-CF6 antibody ameliorated insulin resistance.
Conclusions: CF6 regulates cytosolic pH by interacting with ecto-F1Fo complex and may link tissue acidosis to the mechanism for hypertension complicating diabetes.
- © 2010 by American Heart Association, Inc.