Experiments were designed to examine the effect of oxidized low density lipoproteins (Ox-LDLs) on the expression and the release of endothelin from cultured endothelial cells and intact blood vessels. Ox-LDLs (30-300 jtg/ml), but not native low density lipoproteins (200 ,ug/ml), stimulated the expression of preproendothelin mRNA in porcine and human endothelial cells, leading to a time-and concentrationdependent release of the peptide into the culture medium. The Ox-LDL-stimulated release of endothelin was mimicked by acetylated low density lipoprotein and abolished by downregulation of protein kinase C by phorbol ester. In the intact porcine aorta, Ox-LDLs, but not native low density lipoproteins, also increased the release of peptide in an endothelium-and concentration-dependent manner. The maximal effect was observed at a concentration of 100 ,g/ml. Incubation of the intact porcine aorta with the scavenger receptor antagonist dextran sulfate decreased the formation of endothelin evoked by Ox-LDLs. The Ox-LDL-stimulated production of the peptide was further augmented in the presence of thrombin (4 units/ml) and was unaffected by nitric oxide-generating compound 3-morpholinosydnonimine (10`M).These results suggest that Ox-LDL may be an endogenous mediator of the augmented release of endothelin observed in hyperlipidemia and atherosclerosis. The increased production of the peptide could contribute to vasospastic events and may promote vascular smooth muscle proliferation and progression of atherosclerotic vascular disease.

Essential fatty acid (EFA) deficiency induces fat malabsorption, but the pathophysiological mechanism is unknown. Bile salts (BS) and EFA-rich biliary phospholipids affect dietary fat solubilization and chylomicron formation, respectively. We investigated whether altered biliary BS and/or phospholipid secretion mediate EFA deficiency-induced fat malabsorption in mice. Free virus breed (FVB) mice received EFA-containing (EFA+) or EFA-deficient (EFA−) chow for 8 wk. Subsequently, fat absorption, bile flow, and bile composition were determined. Identical dietary experiments were performed in multidrug resistance gene-2-deficient [ Mdr2(−/−) ] mice, secreting phospholipid-free bile. After 8 wk, EFA−-fed wild-type [ Mdr2(+/+) ] and Mdr2(−/−) mice were markedly EFA deficient [plasma triene (20:3n-9)-to-tetraene (20:4n-6) ratio >0.2]. Fat absorption decreased (70.1 ± 4.2 vs. 99.1 ± 0.3%, P < 0.001), but bile flow and biliary BS secretion increased in EFA− mice compared with EFA+controls (4.87 ± 0.36 vs. 2.87 ± 0.29 μl · min−1 · 100 g body wt−1, P < 0.001, and 252 ± 30 vs. 145 ± 20 nmol · min−1 · 100 g body wt−1, P < 0.001, respectively). BS composition was similar in EFA+- and EFA−-fed mice. Similar to EFA− Mdr2(+/+) mice, EFA− Mdr2(−/−) mice developed fat malabsorption associated with twofold increase in bile flow and BS secretion. Fat malabsorption in EFA− mice is not due to impaired biliary BS or phospholipid secretion. We hypothesize that EFA deficiency affects intracellular processing of dietary fat by enterocytes.

Aging is associated with altered autonomic control of cardiovascular function, but baroreflex function in animal models of aging remains controversial. In this study, pressor and depressor agent-induced reflex bradycardia and tachycardia were attenuated in conscious old (24 mo) rats [57 and 59% of responses in young (10 wk) Wistar rats, respectively]. The intrinsic heart rate (HR, 339 +/- 5 vs. 410 +/- 10 beats/min) was reduced in aged animals, but no intergroup differences in resting mean arterial blood pressure (MAP, 112 +/- 3 vs. 113 +/- 5 mmHg) or HR (344 +/- 9 vs. 347 +/- 9 beats/min) existed between old and young rats, respectively. The aged group also exhibited a depressed (49%) parasympathetic contribution to the resting HR value (vagal effect) but preserved sympathetic function after intravenous methylatropine and propranolol. An implantable electrode revealed tonic renal sympathetic nerve activity (RSNA) was similar between groups. However, old rats showed impaired baroreflex control of HR and RSNA after intravenous nitroprusside (-0.63 +/- 0. 18 vs. -1.84 +/- 0.4 bars x cycle(-1) x mmHg(-1) x s(-1)). Therefore, aging in rats is associated with 1) preserved baseline MAP, HR, and RSNA, 2) impaired baroreflex control of HR and RSNA, and 3) altered autonomic control of resting HR.

. Essential fatty acid deficiency in mice is associated with hepatic steatosis and secretion of large VLDL particles. Am J Physiol Gastrointest Liver Physiol 288: G1150 -G1158, 2005. First published January 20, 2005 doi:10.1152/ajpgi.00456.2004.-Essential fatty acid (EFA) deficiency in mice decreases plasma triglyceride (TG) concentrations and increases hepatic TG content. We evaluated in vivo and in vitro whether decreased hepatic secretion of TG-rich very low-density lipoprotein (VLDL) contributes to this consequence of EFA deficiency. EFA deficiency was induced in mice by feeding an EFAdeficient (EFAD) diet for 8 wk. Hepatic VLDL secretion was quantified in fasted EFAD and EFA-sufficient (EFAS) mice using the Triton WR-1339 method. In cultured hepatocytes from EFAD and EFAS mice, VLDL secretion into medium was measured by quantifying [3 H]-labeled glycerol incorporation into TG and phospholipids. Hepatic expression of genes involved in VLDL synthesis and clearance was measured, as were plasma activities of lipolytic enzymes. TG secretion rates were quantitatively similar in EFAD and EFAS mice in vivo and in primary hepatocytes from EFAD and EFAS mice in vitro. However, EFA deficiency increased the size of secreted VLDL particles, as determined by calculation of particle diameter, particle sizing by light scattering, and evaluation of the TG-to-apoB ratio. EFA deficiency did not inhibit hepatic lipase and lipoprotein lipase activities in plasma, but increased hepatic mRNA levels of apoAV and apoCII, both involved in control of lipolytic degradation of TG-rich lipoproteins. EFA deficiency does not affect hepatic TG secretion rate in mice, but increases the size of secreted VLDL particles. Present data suggest that hypotriglyceridemia during EFA deficiency is related to enhanced clearance of altered VLDL particles. hepatic lipoprotein secretion; lipoprotein clearance; hypotriglyceridemia DEVELOPMENT OF HEPATIC STEATOSIS is a well-established manifestation of essential fatty acid (EFA) deficiency in animal models. It was first described in 1958 in rats by Alfin-Slater and Bernick (3) and in 1970 by Fukazawa et al. (12) and Sinclair and Collins (43). The excess lipid deposited in the liver during EFA deficiency can theoretically result from increased uptake of circulating lipids, enhanced de novo lipogenesis, decreased fatty acid oxidation, or decreased hepatic lipoprotein secretion, or from a combination of these. Increased hepatic lipogenesis and decreased fatty acid oxidation could indeed contribute, because polyunsaturated fatty acids are physiological suppressors of fatty acid synthesis (4, 31) through downregulation of SREBP1c (16, 42, 51) and inducers of hepatic fatty acid oxidation through activation of PPAR␣, respectively. The quantitative contribution of increased lipogenesis and decreased oxidation to EFA deficiency-induced hepatic steatosis has not been established. Whereas the effects of EFA deficiency on induction of hepatic steatosis are fairly consistent in the literature, the consequences for he...