Abstract-The metabolic syndrome is a common precursor of cardiovascular disease and type 2 diabetes that is characterized by the clustering of insulin resistance, dyslipidemia, and increased blood pressure. In humans, mutations in the peroxisome proliferator-activated receptor-␥ (PPAR␥) have been reported to cause the full-blown metabolic syndrome, and drugs that activate PPAR␥ have proven to be effective agents for the prevention and treatment of insulin resistance and type 2 diabetes. Here we report that telmisartan, a structurally unique angiotensin II receptor antagonist used for the treatment of hypertension, can function as a partial agonist of PPAR␥; influence the expression of PPAR␥ target genes involved in carbohydrate and lipid metabolism; and reduce glucose, insulin, and triglyceride levels in rats fed a high-fat, high-carbohydrate diet. None of the other commercially available angiotensin II receptor antagonists appeared to activate PPAR␥ when tested at concentrations typically achieved in plasma with conventional oral dosing. In contrast to ordinary antihypertensive and antidiabetic agents, molecules that can simultaneously block the angiotensin II receptor and activate PPAR␥ have the potential to treat both hemodynamic and biochemical features of the metabolic syndrome and could provide unique opportunities for the prevention and treatment of diabetes and cardiovascular disease in high-risk populations. Key Words: receptors, angiotensin II Ⅲ angiotensin II Ⅲ renin-angiotensin system Ⅲ insulin resistance Ⅲ losartan A ll currently available classes of antihypertensive drugs were developed before it was widely recognized that increased blood pressure is closely associated with insulin resistance and dyslipidemia and well before public health authorities established diagnostic criteria for the metabolic syndrome. 1-3 Thus, the antihypertensive drugs in use today were designed primarily to affect cellular and biochemical mechanisms contributing to increased blood pressure and not to address the disordered carbohydrate and lipid metabolism that often accompany hypertension as part of the metabolic syndrome. Given the major impact of the metabolic syndrome on cardiovascular disease morbidity and mortality, 4 -6 the availability of antihypertensive agents that also improve insulin resistance and dyslipidemia could be of considerable clinical value.Numerous studies have demonstrated that the peroxisome proliferator-activated receptor-␥ (PPAR␥) plays an important role in regulating carbohydrate and lipid metabolism and that ligands for PPAR␥ can improve insulin sensitivity, reduce triglyceride levels, and decrease the risk for atherosclerosis. 7-15 PPAR␥ ligands also have modest antihypertensive effects related at least in part to their ability to promote peripheral vasodilation. 16 -19 Several thiazolidinedione ligands for PPAR␥ have been approved for the treatment of type 2 diabetes; however, these agents have limited capacity to reduce blood pressure and can provoke fluid retention, weight gain, edema, a...

Abstract. The micromeres that arise at the fourth cell division in developing sea urchin embryos give rise to primary mesenchyme, which in turn differentiates and produces calcareous endoskeletal spicules. These spicules have been isolated and purified from pluteus larvae by washing in combinations of ionic and nonionic detergents followed by brief exposure to sodium hypochlorite. The spicules may be demineralized and the integral matrix dissolves. The matrix is composed of a limited number of glycoproteins rich in aspx, glux, gly, ser, and ala, a composition not unlike that found in matrix proteins of biomineralized tissues of molluscs, sponges, and arthropods. There is no evidence for collagen as a component of the matrix. The matrix contains N-linked glycoproteins of the complex type. The matrix arises primarily from proteins synthesized from late gastrulation onward, during the time that spicule deposition occurs. The mixture of proteins binds calcium and is an effective immunogen. Electrophoresis of the glycoproteins on SDS-conraining acrylamide gels, followed by blotting and immunocytochemical detection, reveals major components of ~47, 50, 57, and 64 kD, and several minor components. These same components may be detected with silver staining or fluorography of amino acid-labeled proteins. In addition to providing convenient molecular marker for the study of the development of the micromere lineage, the spicule matrix glycoproteins provide an interesting system for investigations in biomineralization.W E report here our initial results on purification and characterization of the organic matrix of the endoskeletal spicule of the sea urchin embryo. The pluteus larva has calcareous rods, which are intracellular deposits of calcite (mainly CaCO3 and some MgCO3 on an organic ground substance; Benson et al., 1983). The matrix of the skeletal element is of interest because of its probable role in the biomineralization process and because of the obvious parallel between biomineralization of hydroxylapatite in vertebrates and calcite in marine invertebrates. An equally important consideration is the opportunity the spicule presents to study the determination and differentiation of the micromere lineage, a group of cells whose developmental history is very well known. At the fourth cell division in the sea urchin embryo four micromeres arise at the vegetal pole. These micromeres give rise to primary mesenchyme cells, which in turn differentiate into the skeletal spicules (reviewed by Wilt et al., 1985). Micromeres may be isolated from the embryo and will differentiate autonomously in culture to form spicules (Okazaki, 1975). Hence, information on the matrix of the spicules may be useful in the study of tissuespecific differentiation in sea urchin embryos. We have devised ways to purify the matrix of the spicule, and the data support the conclusion that the matrix is composed of a small number of soluble N-linked glycoproteins that have a strong biochemical similarity to acidic proteins present in calcareous structur...