High-density lipoprotein (HDL) cholesterol levels are inversely associated with risk of atherosclerotic cardiovascular disease. At least 50% of the variation in HDL cholesterol levels is genetically determined, but the genes responsible for variation in HDL levels have not been fully elucidated. Lipoprotein lipase (LPL) and hepatic lipase (HL), two members of the triacylglyerol (TG) lipase family, both influence HDL metabolism and the HL (LIPC) locus has been associated with variation in HDL cholesterol levels in humans. We describe here the cloning and in vivo functional analysis of a new member of the TG lipase family. In contrast to other family members, this new lipase is synthesized by endothelial cells in vitro and thus has been termed endothelial lipase (encoded by the LIPG gene). EL is expressed in vivo in organs including liver, lung, kidney and placenta, but not in skeletal muscle. In contrast to LPL and HL, EL has a lid of only 19 residues. EL has substantial phospholipase activity, but less triglyceride lipase activity. Overexpression of EL in mice reduced plasma concentrations of HDL cholesterol and its major protein apolipoprotein A-I. The endothelial expression, enzymatic profile and in vivo effects of EL suggest that it may have a role in lipoprotein metabolism and vascular biology.
Microinjection of L-glutamate into the intermediate nucleus tractus solitarii in anesthetized rats elicits hypotension, bradycardia, and apnea, simulating baroreceptor reflexes. Ablation of the nodose ganglion results in selective reduction of high-affinity uptake of L-glutanate in the nucleus tractus solitarii. L-Glutamate may be the neurotransmitter of afferent nerve fibers from arterial baroreceptors.
Angiotensin (ANG) can produce a biphasic arterial pressure response, i.e., an increase followed by a decrease. Because ANG type 1 (AT1) receptors mediate the pressor response to ANG, we hypothesized that the opposing depressor action is mediated by the ANG type 2 (AT2) receptors. In thiobutabarbital (Inactin)-anesthetized rats bolus injections of angiotensin III (ANG III; 100, 300, and 1,000 ng/kg iv) produced peak increases in MAP at 20 s of 13.4 +/- 1.4, 20.1 +/- 2, and 27.5 +/- 2.8 mmHg and maximum decreases in pressure at 120 s of -6.3 +/- 1.5, -6.8 +/- 2.2, and -11.4 +/- 4.9 mmHg. During blockade of the AT1 receptors with DuP 753 (losartan, 10 mg/kg) the increases in MAP were eliminated (P < 0.01), whereas the depressor responses (-24.7 +/- 8, -32.8 +/- 9.3, and -42.0 +/- 10.0 mmHg) were significantly (P < 0.05) larger. In separate groups of rats, combined blockade of both AT1 and AT2 receptors eliminated all changes in MAP in response to ANG III, whereas blockade of AT2 receptors alone enhanced the pressor response to ANG III. During AT1 receptor blockade angiotensin II also caused consistent decreases in pressure, which were inhibited during combined blockade of AT1 and AT2 receptors. Therefore, we have demonstrated that the AT2 receptors mediate a depressor response to ANG.
Tyrphostins are low-molecular-weight synthetic inhibitors of protein tyrosine kinase, which block cell proliferation. Since platelet-derived growth factor (PDGF) is thought to figure prominently in disorders of vascular smooth muscle cells (VSMC), such as atherosclerosis, hypertension, and restenosis, we examined whether tyrphostins would inhibit PDGF-induced mitogenesis in VSMC. In this communication, we demonstrate that tyrphostins with the benzenemalononitrile nucleus inhibited PDGF-dependent growth of VSMC as well as PDGF-dependent DNA synthesis in these cells, with the concentrations for 50% inhibition ranging from 0.04 to 9 microM. Up to 30-fold higher tyrphostin concentrations were required to inhibit serum-stimulated DNA synthesis of VSMC. The effect of the tyrphostins is reversible, since on their removal a normal proliferative response to PDGF was resumed. Tyrphostins also inhibited PDGF-receptor autophosphorylation and PDGF-induced phosphorylation of intracellular substrates, including the phosphorylation of phospholipase C-gamma, with a potency ratio similar to their antimitogenic activity. The expression of c-fos mRNA, a mitogenic nuclear signal, was also reduced in PDGF-stimulated VSMC treated with tyrphostins at concentrations which inhibit PDGF-induced mitogenesis. It is concluded that tyrphostins are potent reversible inhibitors of PDGF-induced mitogenesis which act by inhibiting the tyrosine kinase activity of the PDGF receptor and the subsequent signaling cascade. Tyrphostins may be useful in the study and treatment of VSMC proliferation disorders.
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