Essential hypertension is frequently associated with the clustering of multiple risk factors for diabetes and cardiovascular disease including insulin resistance, dyslipidemia, as well as increased blood pressure. This clustering of multiple risk factors for heart disease and diabetes is often referred to as the metabolic syndrome and is reported to affect 25% of the general population and as many as 50% of patients with hypertension. It is well established that weight loss and exercise can be effective in ameliorating hypertension, diabetes, and the metabolic syndrome, however, such life style modifications are often difficult to achieve in clinical practice. Moreover, many patients with hypertension or obesity do not develop the metabolic syndrome or diabetes. Thus, it is hoped that the identification of genetic mechanisms that predispose patients to developing the hypertension metabolic syndrome will ultimately help guide development of new approaches to prevention and therapy. The spontaneously hypertensive rat (SHR) is the most widely studied genetic model of hypertension and like humans with essential hypertension, exhibits a number of abnormalities in carbohydrate and lipid metabolism that represent risk factors for cardiovascular disease. The use of congenic and transgenic models of the SHR has proven to be successful in isolating nuclear gene variants that contribute to increased blood pressure and biochemical features of the metabolic syndrome in experimental hypertension. Recently, it has been hypothesized that variation in the mitochondrial genome may also play an important role in hypertension, the metabolic syndrome, and related disorders including type 2 diabetes. However, despite tantalizing results from human studies, progress in testing the mitochondria DNA (mtDNA) hypothesis has been limited because few animal models have been available for directly investigating the effects of mtDNA variants on biochemical or hemodynamic features of the metabolic syndrome. To address this problem, we have derived novel models of the SHR with identical nuclear genomes but different mitochondrial genomes. For example, the SHR-mtBN conplastic strain carries the mitochondrial genome of the BN strain on the SHR background and is genetically identical to the SHR progenitor strain except for defined differences in their mitochondrial genomes. Using these new models, we have also identified sequence variants in mtDNA linked to effects on mitochondrial function, insulin sensitivity, and biochemical features of the metabolic syndrome. In the current studies, we will capitalize on these unique models to directly investigate the mtDNA hypothesis and determine the molecular and cellular mechanisms whereby sequence variation in the mitochondrial genome contributes to the pathogenesis of hypertension and the metabolic syndrome Hypertension is frequently associated with the clustering of multiple risk factors for diabetes and heart disease including abnormalities in glucose and fat metabolism as well as increased blood pressure. This clustering of multiple risk factors for diabetes and heart disease is referred to as the metabolic syndrome and affects 25% of the general population and as many as 50% of patients with hypertension. This project is designed to investigate genetic factors that influence the development of the metabolic syndrome and ultimately help identify new targets for prevention and treatment of diabetes and cardiovascular disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL056028-15
Application #
8230451
Study Section
Hypertension and Microcirculation Study Section (HM)
Program Officer
OH, Youngsuk
Project Start
1997-01-01
Project End
2014-01-31
Budget Start
2012-02-01
Budget End
2014-01-31
Support Year
15
Fiscal Year
2012
Total Cost
$382,388
Indirect Cost
$134,888
Name
University of California San Francisco
Department
Pathology
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Pravenec, Michal; Kozich, Viktor; Krijt, Jakub et al. (2013) Folate deficiency is associated with oxidative stress, increased blood pressure, and insulin resistance in spontaneously hypertensive rats. Am J Hypertens 26:135-40
Neckar, Jan; Silhavy, Jan; Zidek, Vaclav et al. (2012) CD36 overexpression predisposes to arrhythmias but reduces infarct size in spontaneously hypertensive rats: gene expression profile analysis. Physiol Genomics 44:173-82
Houstek, Josef; Hejzlarova, Katerina; Vrbacky, Marek et al. (2012) Nonsynonymous variants in mt-Nd2, mt-Nd4, and mt-Nd5 are linked to effects on oxidative phosphorylation and insulin sensitivity in rat conplastic strains. Physiol Genomics 44:487-94
Pravenec, Michal; Kajiya, Takashi; Zidek, Vaclav et al. (2011) Effects of human C-reactive protein on pathogenesis of features of the metabolic syndrome. Hypertension 57:731-7
Pravenec, Michal; Zidek, Vaclav; Landa, Vladimir et al. (2011) Age-related autocrine diabetogenic effects of transgenic resistin in spontaneously hypertensive rats: gene expression profile analysis. Physiol Genomics 43:372-9
Malinska, Hana; Oliyarnyk, Olena; Hubova, Miriam et al. (2010) Increased liver oxidative stress and altered PUFA metabolism precede development of non-alcoholic steatohepatitis in SREBP-1a transgenic spontaneously hypertensive rats with genetic predisposition to hepatic steatosis. Mol Cell Biochem 335:119-25
Johnson, Michelle D; He, Liqun; Herman, Daniel et al. (2009) Dissection of chromosome 18 blood pressure and salt-sensitivity quantitative trait loci in the spontaneously hypertensive rat. Hypertension 54:639-45
Pravenec, M; Kazdova, L; Maxova, M et al. (2008) Long-term pioglitazone treatment enhances lipolysis in rat adipose tissue. Int J Obes (Lond) 32:1848-53
Kurtz, Theodore W; Pravenec, Michal (2008) Molecule-specific effects of angiotensin II-receptor blockers independent of the renin-angiotensin system. Am J Hypertens 21:852-9
Sugimoto, Ken; Kazdova, Ludmila; Qi, Nathan R et al. (2008) Telmisartan increases fatty acid oxidation in skeletal muscle through a peroxisome proliferator-activated receptor-gamma dependent pathway. J Hypertens 26:1209-15

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