Coupling factor 6-induced activation of ecto-F1Fo complex induces insulin resistance, mild glucose intolerance and elevated blood pressure in mice

Abstract

Aims/hypothesis Despite advances in pharmacological treatments, diabetes with hypertension continues to be a major public health problem with high morbidity and mortality rates. We recently identified a circulating peptide coupling factor 6 (CF6), which binds to the plasma membrane ATP synthase (ecto-F 1 F o complex), resulting in intracellular acidosis. We investigated whether overexpression of CF6 contributes to diabetes and hypertension by intracellular acidosis. Methods Transgenic mice overexpressing CF6 (also known as ATP5J) were generated, and physiological, biochemical and molecular biology studies were performed. Results CF6 overexpression elicited a sustained decrease in intracellular pH in tissues (aorta, kidney, skeletal muscle and liver, with the exception of adipose tissue) that express its receptor, the β-subunit of ecto-F 1 F o complex. Consistent with the receptor distribution, phospho-insulin receptor β, phosphoinositide 3-kinase activity and the phospho-Akt1: total Akt1 ratio were all decreased in the skeletal muscle and the liver in transgenic compared with wild-type mice, resulting in a decrease of plasma membrane-bound GLUT4 and an increase in hepatic glucose production. Under a high-sucrose diet, transgenic mice had insulin resistance and mild glucose intolerance; under a high-salt diet, they had elevated blood pressure with increased renal RASrelated C3 botulinum substrate 1 (RAC1)-GTP, which is an activator of mineralocorticoid receptor. Conclusions/interpretation Through its action on the β-subunit of ecto-F 1 F o complex, which results in intracellular acidosis, CF6 plays a crucial role in the development of insulin resistance and hypertension. This finding might advance our understanding of the mechanisms underlying diabetes and hypertension, possibly also providing a novel therapeutic target against cardiovascular disease.

Estrogen attenuates coupling factor 6-induced salt-sensitive hypertension and cardiac systolic dysfunction in mice

“…However, CF6 attenuates prostacyclin generation via the inhibition of cytosolic phospholipase A 2 , 16 nitric oxide generation via the upregulation of asymmetric dimethylarginine or the inhibition of endothelial nitric oxide synthase phosphorylation 45,46 and the PI3K/Akt cascade. 24 Therefore, the rapid effects of estrogen, such as the increase in nitric oxide and the induction of the PI3K-Akt cascade, may antagonize the action of CF6. This issue remains to be clarified in a future study.…”

“…Characterization of the TG mice is described elsewhere. 24 Briefly, the gene expression of CF6 mRNA was upregulated by 1.94 ± 0.27 times in body tissues, such as the heart, pancreas, spleen, kidneys and stomach, in TG mice compared with WT mice. The plasma level of total (human plus mouse) CF6 was twice as high in TG mice as in WT mice.…”

Coupling factor 6 attenuates CXCR4 expression through the HIF-1α and c-Src pathways and promotes endothelial apoptosis and inflammation

“…Briefly, the introduced gene product was released outside of the cells by a secretion signal upstream from the mature human CF6 (Asn33-Ala108) and was expressed in overall tissues by the human elongation factor 1 promoter. CF6 mRNA expression was 7 upregulated by 1.94±0.27 times in overall tissues, including the heart and kidney, in the TG compared with wild-type mice (WT), and the plasma level of total CF6 was twice as high in the TG as in the WT (11). The intracellular pH value, as measured by 31 P-magnetic resonance spectroscopy, was decreased by 0.1 unit in skeletal muscle and liver of the TG (11).…”

“…CF6 mRNA expression was 7 upregulated by 1.94±0.27 times in overall tissues, including the heart and kidney, in the TG compared with wild-type mice (WT), and the plasma level of total CF6 was twice as high in the TG as in the WT (11). The intracellular pH value, as measured by 31 P-magnetic resonance spectroscopy, was decreased by 0.1 unit in skeletal muscle and liver of the TG (11). For histological analysis, mice were sacrificed killed by cervical dislocation under anesthesia with intraperitoneal administration of 0.3 mg/kg medetomidine, 4 mg/kg midazolam, and 5 mg/kg butorphanol.…”

Mitochondrial coupling factor 6 upregulation in hypertension-induced cardiac hypertrophy

“…CF6 functions are believed to be mediated by CF6 binding to the plasma membrane-bound ATP synthase, ecto-F1F0 complex, resulting in proton import and acidosis, whichin turn increases activated Rac1, a member of the Rho family of GTPases [3]. CF6 has several functions: it acts as a pro-atherogenic molecule in the cardiovascular system [4], regulated by estrogen in saltsensitive hypertension and cardiac systolic dysfunction in mice [3]; it attenuates exercise-induced physiological cardiac hypertrophy by inhibiting PI3K/Akt signaling in mice [5]; it plays a crucial role in the development of insulin resistance and hypertension [6]; and it appears to be a novel molecule for the pathogenesis and treatment of stroke [7]. Studies have shown an elevated plasma level of CF6 in patients with essential hypertension, diabetes mellitus, end-stage renal disease, acute myocardial infarction, and coronary heart disease [8]; however, research on CF6 in spontaneously hypertensive rats (SHRs) is mainly in vascular smooth muscle cells (VSMCs) and vascular endothelial cells [9,10].…”