The tone of vascular smooth muscle cells is a primary determinant of the total peripheral vascular resistance and hence the arterial blood pressure. Most forms of hypertension ultimately result from an increased vascular tone that leads to an elevated total peripheral resistance. Regulation of vascular resistance under normotensive and hypertensive conditions involves multiple mediators, many of which act through G protein-coupled receptors on vascular smooth muscle cells. Receptors that mediate vasoconstriction couple with the G-proteins G(q)-G11 and G12-G13 to stimulate phosphorylation of myosin light chain (MLC) via the Ca2+/MLC kinase- and Rho/Rho kinase-mediated signaling pathways, respectively. Using genetically altered mouse models that allow for the acute abrogation of both signaling pathways by inducible Cre/loxP-mediated mutagenesis in smooth muscle cells, we show that G(q)-G11-mediated signaling in smooth muscle cells is required for maintenance of basal blood pressure and for the development of salt-induced hypertension. In contrast, lack of G12-G13, as well as of their major effector, the leukemia-associated Rho guanine nucleotide exchange factor (LARG), did not alter normal blood pressure regulation but did block the development of salt-induced hypertension. This identifies the G12-G13-LARG-mediated signaling pathway as a new target for antihypertensive therapies that would be expected to leave normal blood pressure regulation unaffected.

Nicotinic acid (niacin) is a drug used to reduce the progression of atherosclerosis. Its antiatherosclerotic activity is believed to result from lipid-modifying effects, including its ability to decrease LDL cholesterol and increase HDL cholesterol levels in plasma. Here, we report that in a mouse model of atherosclerosis, we found that nicotinic acid inhibited disease progression under conditions that left total cholesterol and HDL cholesterol plasma levels unaffected. The antiatherosclerotic effect was not seen in mice lacking the receptor for nicotinic acid GPR109A. Surprisingly, transplantation of bone marrow from GPR109A-deficient mice into atherosclerosis-prone animals also abrogated the beneficial effect of nicotinic acid. We detected expression of GPR109A in macrophages in atherosclerotic plaques. In macrophages from WT mice, but not from GPR109A-deficient animals, nicotinic acid induced expression of the cholesterol transporter ABCG1 and promoted cholesterol efflux. Furthermore, activation of GPR109A by nicotinic acid inhibited MCP-1-induced recruitment of macrophages into the peritoneal cavity and impaired macrophage recruitment to atherosclerotic plaques. In contrast with current models, our data show that nicotinic acid can reduce the progression of atherosclerosis independently of its lipid-modifying effects through the activation of GPR109A on immune cells. We conclude therefore that GPR109A mediates antiinflammatory effects, which may be useful for treating atherosclerosis and other diseases.

The antidyslipidemic drug nicotinic acid and the antipsoriatic drug monomethyl fumarate induce cutaneous flushing through activation of G protein-coupled receptor 109A (GPR109A). Flushing is a troublesome side effect of nicotinic acid, but may be a direct reflection of the wanted effects of monomethyl fumarate. Here we analyzed the mechanisms underlying GPR109A-mediated flushing and show that both Langerhans cells and keratinocytes express GPR109A in mice. Using cell ablation approaches and transgenic cell type-specific GPR109A expression in Gpr109a -/-mice, we have provided evidence that the early phase of flushing depends on GPR109A expressed on Langerhans cells, whereas the late phase is mediated by GPR109A expressed on keratinocytes. Interestingly, the first phase of flushing was blocked by a selective cyclooxygenase-1 (COX-1) inhibitor, and the late phase was sensitive to a selective COX-2 inhibitor. Both monomethyl fumarate and nicotinic acid induced PGE 2 formation in isolated keratinocytes through activation of GPR109A and COX-2. Thus, the early and late phases of the GPR109A-mediated cutaneous flushing reaction involve different epidermal cell types and prostanoid-forming enzymes. These data will help to guide new efficient approaches to mitigate nicotinic acid-induced flushing and may help to exploit the potential antipsoriatic effects of GPR109A agonists in the skin.

Niacin (nicotinic acid) has recently been shown to increase serum adiponectin concentrations in men with the metabolic syndrome. However, little is known about the mechanism(s) by which niacin regulates the intracellular trafficking and secretion of adiponectin. Since niacin appears to exert its effects on lipolysis through receptor (GPR109A)-dependent and -independent pathways, the purpose of this investigation was to examine the role of the recently identified GPR109A receptor in adiponectin secretion. Initial in vivo studies in rats demonstrated that niacin (30 mg/kg po) acutely increases serum adiponectin concentrations, whereas it decreases NEFAs. Further in vitro studies demonstrated an increase in adiponectin secretion and a decrease in lipolysis in primary adipocytes following treatment with niacin or ␤-hydroxybutyrate (an endogenous ligand of the GPR109A receptor), but these effects were blocked when adipocytes were pretreated with pertussis toxin. Niacin had no effect on adiponectin secretion or lipolysis in 3T3-L1 adipocytes, which have limited cell surface expression of the GPR109A receptor. To further substantiate these in vitro findings, wild-type and GPR109A receptor knockout mice were administered a single dose of niacin or placebo, and serum was obtained for the determination of adiponectin and NEFA concentrations. Serum adiponectin concentrations increased and serum NEFAs decreased in the wild-type mice within 10 min following niacin administration. However, niacin administration had no effect on adiponectin and NEFA concentrations in the GPR109A receptor knockout mice. These results demonstrate that the GPR109A receptor plays an important role in the dual regulation of adiponectin secretion and lipolysis. nicotinic acid; PUMA-G; HM74A; nonesterified fatty acids; lipolysis NIACIN (NICOTINIC ACID) HAS BEEN USED for more than 50 years as a pharmacological agent for the treatment of dyslipidemia and remains an effective strategy to decrease serum triglycerides and increase HDL cholesterol concentrations (6,19). In one of the first randomized clinical trials of heart disease prevention, niacin reduced serum triglyceride concentrations by 27% and nonfatal myocardial infarctions and cardiovascular disease (CVD) mortality by 27 and 26%, respectively (6a). More recent studies provide evidence that niacin is associated with a reduction in the number of angiographically documented vascular lesions and carotid artery intima-media thickness in patients with CVD (16, 31).The cardioprotective benefits of niacin have been attributed primarily to improvements in blood lipid and lipoprotein characteristics and reductions in vascular inflammation and thrombosis (18). However, recent studies have demonstrated that niacin significantly modulates serum adipokine concentrations. Westphal et al. (36) demonstrated that 6 wk of niacin treatment increased serum adiponectin concentrations by 54% in obese men with the metabolic syndrome. Investigations from our laboratory support these findings and further demonstrate th...

Background-Cardiac remodeling in response to pressure or volume overload plays an important role in the pathogenesis of heart failure. Various mechanisms have been suggested to translate mechanical stress into structural changes, one of them being the release of humoral factors such as angiotensin II and endothelin-1, which in turn promote cardiac hypertrophy and fibrosis. A large body of evidence suggests that the prohypertrophic effects of these factors are mediated by receptors coupled to the G q/11 family of heterotrimeric G proteins. Most G q/11 -coupled receptors, however, can also activate G proteins of the G 12/13 family, but the role of G 12/13 in cardiac remodeling is not understood. Methods and Results-We use siRNA-mediated knockdown in vitro and conditional gene inactivation in vivo to study the role of the G 12/13 family in pressure overload-induced cardiac remodeling. We show in detail that inducible cardiomyocyte-specific inactivation of the ␣ subunit of G 13 , G␣ 13 , does not affect basal heart function but protects mice from pressure overload-induced hypertrophy and fibrosis as efficiently as inactivation of G␣ q/11 . Furthermore, inactivation of G␣ 13 prevents the development of heart failure up to 1 year after overloading. On the molecular level, we show that G␣ 13 , but not G␣ q/11 , controls agonist-induced expression of hypertrophy-specific genes through activation of the small GTPase RhoA and consecutive activation of myocardin-related transcription factors. Conclusion-Our data show that the G 12/13 family of heterotrimeric G proteins is centrally involved in pressure overload-induced cardiac remodeling and plays a central role in the transition to heart failure.