Mitochondrial coupling factor 6 as a potent endogenous vasoconstrictor

Abstract

We demonstrated recently that coupling factor 6, an essential component of the energy-transducing stalk of mitochondrial ATP synthase, suppresses the synthesis of prostacyclin in vascular endothelial cells. Here, we tested the hypothesis that coupling factor 6 is present on the cell surface and is involved in the regulation of systemic circulation. This peptide is present on the surface of CRL-2222 vascular endothelial cells and is released by these cells into the medium. In vivo, the peptide circulates in the vascular system of the rat, and its gene expression and plasma concentration are higher in spontaneously hypertensive rats (SHRs) than in normotensive controls. Elevation of blood pressure with norepinephrine did not affect the plasma concentration of coupling factor 6. Intravenous injection of recombinant peptide increased blood pressure, apparently by suppressing prostacyclin synthesis, whereas a specific Ab to coupling factor 6 decreased systemic blood pressure concomitantly with an increase in plasma prostacyclin. Interestingly, the antibody's hypotensive effect could be abolished by treating with the cyclooxygenase inhibitor indomethacin. These findings indicate that mitochondrial coupling factor 6 functions as a potent endogenous vasoconstrictor in the fashion of a circulating hormone and may suggest a new mechanism for hypertension.

Mitochondrial coupling factor 6 upregulation in hypertension-induced cardiac hypertrophy

“…Recently, CF6 was shown to have multiple extracellular roles as a circulating hormone [1]. CF6 increases arterial blood pressure in rats, which is consistent with the high levels of CF6 seen in the plasma of patients diagnosed with hypertension [2].…”

“…CF6 is an endogenous inhibitor of prostacyclin synthesis that suppresses the synthesis of prostacyclin via inhibition of cytosolic phospholipase A2 [21]; moreover, injected CF6 induces an increase in arterial blood pressure [1]. Since CF6 is present on the surface of vascular endothelial cells and is released outside the cells by mechanical forces such as shear stress [22,23], hypertension may be involved in the increase in…”

“…In brief, the supernatants obtained from the myocardial tissue homogenate after centrifugation (3,000 rpm, 10 min) were addTao He 1,2 · Aili Guan 2 · Yue Shi 2 · Zhiming Ge 1 · Hongyan Dai 2 1 ed to a CF6-antibody-coated plate and incubated at room temperature for 2 h. After adding stop solution, we read the absorbance of each microwell on a spectrophotometer using 450 nm as the primary wavelength. The measurement of CF6 was duplicated.…”

“…Mitochondrial coupling factor 6 (CF6) is a component of the peripheral stalk of ATP synthase, which is considered essential for energy transduction [1]. Recently, CF6 was shown to have multiple extracellular roles as a circulating hormone [1].…”

Troglitazone and 15-deoxy-Δ-prostaglandin J inhibit shear-induced coupling factor 6 release in endothelial cells

“…We recently demonstrated that CF6 is present not only in the mitochondria but also on the surface of human vascular endothelial cells and is released outside of the cells by mechanical forces such as shear stress [4] and by tumor necrosis factor a (TNF-a) [5]. We further showed that CF6 is an endogenous inhibitor of prostacyclin synthesis in human vascular endothelial cells and functions as an endogenous vasoconstrictor peptide in rats [6,7]. More recently, we showed that circulating CF6 is elevated in human hypertension and modulated by salt intake presumably via reactive oxygen species (ROS) [8].…”