Nianning Qi

Identification of Telmisartan as a Unique Angiotensin II Receptor Antagonist With Selective PPARγ–Modulating Activity

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-γ (PPARγ) have been reported to cause the full-blown metabolic syndrome, and drugs that activate PPARγ 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 PPARγ; influence the expression of PPARγ 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 PPARγ 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 PPARγ 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.

Pharmacogenetic evidence that Cd36 is a key determinant of the metabolic effects of pioglitazone

Pioglitazone, like other thiazolidinediones, is an insulin-sensitizing agent that activates the peroxisome proliferator-activated receptor γ and influences the expression of multiple genes involved in carbohydrate and lipid metabolism. However, it is unknown which of these many target genes play primary roles in determining the antidiabetic and hypolipidemic effects of thiazolidinediones. To specifically investigate the role of the Cd36 fatty acid transporter gene in the insulin-sensitizing actions of thiazolidinediones, we studied the metabolic effects of pioglitazone in spontaneously hypertensive rats (SHR) that harbor a deletion mutation in Cd36 in comparison to congenic and transgenic strains of SHR that express wild-typeCd36. In congenic and transgenic SHR with wild-typeCd36, administration of pioglitazone was associated with significantly lower circulating levels of fatty acids, triglycerides, and insulin as well as lower hepatic triglyceride levels and epididymal fat pad weights than in SHR harboring mutant Cd36. Additionally, insulin-stimulated glucose oxidation in isolated soleus muscle was significantly augmented in pioglitazone-fed rats with wild-type Cd36 versus those with mutantCd36. The Cd36 genotype had no effect on pioglitazone-induced changes in blood pressure. These findings provide direct pharmacogenetic evidence that in the SHR model, Cd36is a key determinant of the insulin-sensitizing actions of a thiazolidinedione ligand of peroxisome proliferator-activated receptor γ.

Y-Chromosome Transfer Induces Changes in Blood Pressure and Blood Lipids in SHR

Abstract—Previous studies with chromosome-Y consomic strains of spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats suggest that a quantitative trait locus for blood pressure regulation exists on chromosome Y. To test this hypothesis in the SHR–Brown Norway (BN) model and to study the effects of chromosome Y on lipid and carbohydrate metabolism, we produced a new consomic strain of SHR carrying the Y chromosome transferred from the BN rat. We found that replacing the SHR Y chromosome with the BN Y chromosome resulted in significant decreases in systolic and diastolic blood pressures in the SHR.BN-Y consomic strain (P <0.05). To elicit possible dietary-induced variation in lipid and glucose metabolism between the SHR progenitor and chromosome-Y consomic strains, we fed rats a high-fructose diet for 15 days in addition to the normal diet. On the high-fructose diet, the SHR.BN-Y consomic rats exhibited significantly increased levels of serum triglycerides and decreased levels of serum HDL cholesterol versus the SHR progenitor rats. Glucose tolerance and insulin/glucose ratios, however, were similar in both strains on both normal and high-fructose diets. These findings provide direct evidence that a gene or genes on chromosome Y contribute to the pathogenesis of spontaneous hypertension in the SHR-BN model. These results also indicate that transfer of the Y chromosome from the BN rat onto the SHR background exacerbates dietary-induced dyslipidemia in SHR. Thus, genetic variation in genes on the Y chromosome may contribute to variation in blood pressure and lipid levels and may influence the risk for cardiovascular disease.

Genetic Analysis of Rat Chromosome 1 and the Sa Gene in Spontaneous Hypertension

Linkage studies in segregating populations derived from the spontaneously hypertensive rat (SHR) indicate that a blood pressure quantitative trait locus exists on rat chromosome 1 in the vicinity of the Sa gene. On the basis of these findings and the observation of increased renal expression of the Sa gene in SHR versus normotensive rats, the Sa gene has been proposed as a candidate gene for spontaneous hypertension. In SHR congenic strains, we and others have found that replacement of a segment of SHR chromosome 1 that contains the Sa gene with the corresponding chromosome segment from a normotensive Brown Norway (BN) rat or Wistar-Kyoto rat can reduce blood pressure. To test whether the Sa gene is necessary for the effect of this region of chromosome 1 on blood pressure, we studied a new SHR congenic subline that harbors a smaller segment of BN chromosome 1 that does not include the Sa gene. Transfer of this subregion of chromosome 1 from the BN rat onto the SHR background was associated with significant reductions in blood pressure comparable to those previously observed on transfer of a larger region of chromosome 1 that included the Sa gene. Thus, in the SHR-BN model of hypertension, the results of these mapping studies (1) demonstrate that molecular variation in the Sa gene is not required for the effect of this region of chromosome 1 on blood pressure and (2) should direct attention toward other candidate genes within the differential chromosome segment of the new congenic subline.

Transgenic Rescue of Defective Cd36 Attenuates Insulin Resistance, Dyslipidemia, and Hypertension in Spontaneously Hypertensive Rats

70 Linkage studies in spontaneously hypertensive rats (SHR) have implicated a host of different DNA sequence variants in the genetic control of blood pressure (BP) and a variety of other cardiovascular phenotypes. However, direct proof that any of these gene variants represents a true quantitative trait locus (QTL) regulating BP or any other complex trait is lacking. To directly test the identity of putative QTL in the SHR model, we have: 1) developed transgenic techniques for rescuing mutant alleles directly on the SHR background and 2) used these techniques to determine whether a gene encoding a fatty acid transporter (Cd36) truly represents a QTL that can influence the clustering of multiple cardiovascular risk factors in spontaneous hypertension. Towards these ends, we have successfully derived multiple transgenic strains of SHR (SHR-TG strains) that express the wild type allele for Cd36 on an SHR background harboring the deletion variant of Cd36 (SHR control). In these strains, low level expression of wild type Cd36 on the mutant SHR background ameliorated glucose intolerance (e.g., area under the GTT curve = 713±21 in the SHR-TG19 strain vs. 954±45 mmol/L/2hr in the SHR control strain, p