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(Hypertension. 2007;49:941.)
© 2007 American Heart Association, Inc.

Novartis Award

Molecular Genetics of Experimental Hypertension and the Metabolic Syndrome

From Gene Pathways to New Therapies

From the Institute of Physiology and Center for Applied Genomics (M.P.), Czech Academy of Sciences, Prague, Czech Republic; and the Department of Laboratory Medicine (T.W.K.), University of California San Francisco.

Correspondence to Theodore W. Kurtz, University of California San Francisco Clinical Laboratories, 185 Berry St, Suite 290, San Francisco, CA 94107. E-mail KurtzT{at}Labmed2.ucsf.edu

Genetic studies of human and experimental hypertension provide a means to identify key pathways that predispose individuals to increased blood pressure and associated risk factors for cardiovascular and metabolic diseases. The pathways so identified can then serve as targets for therapeutic intervention. This article discusses genetic studies in animal models of hypertension in which specific genes have been identified that regulate blood pressure and biochemical features of the metabolic syndrome. Consistent with studies in humans with monogenic disorders of blood pressure regulation, studies in rat models have demonstrated that naturally occurring genetic variation in pathways regulating sodium chloride transport can contribute to inherited variation in blood pressure. Such studies have also indicated that naturally occurring variation in genes, such as Cd36, that regulate fatty acid metabolism and ectopic accumulation of fat and fat metabolites can influence both biochemical and hemodynamic features of the metabolic syndrome and mediate the antidiabetic effects of drugs that activate the peroxisome proliferator-activated receptor-. Angiotensin II receptor blockers with the ability to selectively modulate activity of peroxisome proliferator-activated receptor- and expression of genes in these fat metabolism pathways may represent useful prototypes for a new class of transcription modulating drugs aimed at treating patients with hypertension and the metabolic syndrome.

Key Words: genetics • rats • inbred SHR • metabolic syndrome X • hypertension • angiotensin II type 1 receptor blockers • peroxisome proliferator-activated receptors

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