Citronellal prevents endothelial dysfunction and atherosclerosis in rats.

BACKGROUND: Atherosclerosis is a chronical inflammatory disease in arterial walls, which is involved in oxidative stress and endothelial dysfunction. Aromatherapy is one of the complementary therapies that use essential oils as the major therapeutic agents to treat several diseases. Citronellal (CT) is a monoterpene predominantly formed by the secondary metabolism of plants, producing antithrombotic, antiplatelet, and antihypertensive activities. AIM: The aim of the present study is to explore whether aromatherapy with CT improves endothelial function to prevent the formation of atherosclerotic plaque in vivo. METHODS: An AS model in carotid artery was induced by balloon injury and vitamin D3 injection in rats fed with a high-fat diet. The size of the carotid atherosclerotic plaque was determined by ultrasound, oil red, and hematoxylin-eosin staining. Endothelial function was assessed by measuring acetylcholine-induced vessel relaxation in an organ chamber. RESULTS: Administrations of CT (50, 100, and 150 mg/kg) as well as lovastatin dramatically reduced the size of carotid atherosclerotic plaque in rats in a dose-dependent manner, compared with atherosclerotic rats fed with a high-fat diet plus balloon injury and vitamin D3. Mechanically, CT improved endothelial dysfunction, increased cell migration, and suppressed oxidative stress and inflammation in vascular endothelium in rats feeding on the high-fat diet plus balloon injury. Further, CT downregulated the protein levels of sodium-hydrogen exchanger 1 in rats with atherosclerosis. CONCLUSION: CT improves endothelial dysfunction and prevents the growth of atherosclerosis in rats by reducing oxidative stress. Clinically, CT is potentially considered as a medicine to treat patients with atherosclerosis.

Recovery from hypoxia-induced internalization of cardiac Na+ /H + exchanger 1 requires an adequate intracellular store of antioxidants.

The heart is highly active metabolically but relatively underperfused and, therefore, vulnerable to ischemia. In addition to acidosis, a key component of ischemia is hypoxia that can modulate gene expression and protein function as part of an adaptive or even maladaptive response. Here, using cardiac-derived HL-1 cells, we investigate the effect of various hypoxic stimuli on the expression and activity of Na+ /H + exchanger 1 (NHE1), a principal regulator of intracellular pH. Acute (10 min) anoxia produced a reversible decrease in the sarcolemmal NHE1 activity attributable to NHE1 internalization. Treatment with either 1% O 2 or dimethyloxaloylglycine (DMOG; 1 mM) for 48-hr stabilized hypoxia-inducible factor 1 and reduced the sarcolemmal NHE1 activity by internalization, but without a change in total NHE1 immunoreactivity or message levels of the coding gene ( SLC9A1) determined in whole-cell lysates. Unlike the effect of DMOG, which was rapidly reversed on washout, reoxygenation after a prolonged period of hypoxia did not reverse the effects on NHE1, unless media were also supplemented with a membrane-permeant derivative of glutathione (GSH). Without a prior hypoxic episode, GSH supplementation had no effect on the NHE1 activity. Thus, posthypoxic NHE1 reinsertion can only take place if cells have a sufficient reservoir of a reducing agent. We propose that oxidative stress under prolonged hypoxia depletes intracellular GSH to an extent that curtails NHE1 reinsertion once the hypoxic stimulus is withdrawn. This effect may be cardioprotective, as rapid postischaemic restoration of the NHE1 activity is known to trigger reperfusion injury by producing an intracellular Na + -overload, which is proarrhythmogenic.

Ginsenoside Rg3 Decreases NHE1 Expression via Inhibiting EGF-EGFR-ERK1/2-HIF-1 α Pathway in Hepatocellular Carcinoma: A Novel Antitumor Mechanism.

Na + /H + exchanger 1 (NHE1) plays a vital role in the oncogenesis and development of hepatocellular carcinoma (HCC) and has been regarded as a promising target for the treatment of HCC. Ginsenoside Rg3 (Rg3), a bioactive ginseng compound, is suggested to possess pleiotropic antitumor effects on HCC. However, the underlying mechanisms of Rg3 suppressing HCC remain unclear. In the present study, we uncovered a novel antitumor mechanism of Rg3 on HCC by decreasing NHE1 expression through in vivo and in vitro studies. Mechanistically, we demonstrated that epidermal growth factor (EGF) could dramatically upregulate NHE1 expression, while increasing the phosphorylated extracellular signal-regulated protein kinase (ERK1/2) level and hypoxia-inducible factor 1 alpha (HIF-1 α) expression. In the presence of ERK1/2-specific inhibitor PD98059, EGF stimulated HIF-1 α and NHE1 expression was obviously blocked in addition, the presence of HIF-1 α -specific inhibitor 2-methoxyestradiol (2-MeOE2) blocked EGF stimulated NHE1 expression. Moreover, results from in vivo and in vitro studies indicate that Rg3 treatment markedly decreased the expression of EGF, EGF receptor (EGFR), phosphorylated ERK1/2 and HIF-1 α . Conclusively, these findings suggested that NHE1 was stimulated by EGF, and Rg3 could decrease NHE1 expression by integrally inhibiting EGF-EGFR-ERK1/2-HIF- α signal axis in HCC. Together, our evidence indicated that Rg3 was an effective multi-targets antitumor agent for the treatment of HCC.