Molecular Genetics of Experimental Hypertension and the Metabolic Syndrome

Abstract

Abstract-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 Ⅲ rats Ⅲ inbred SHR Ⅲ metabolic syndrome X Ⅲ hypertension Ⅲ angiotensin II type 1 receptor blockers Ⅲ peroxisome proliferator-activated receptors G enes involved in the pathogenesis of complex clinical disorders including essential hypertension and the metabolic syndrome are often referred to as quantitative trait loci (QTL). Identification of QTL at the molecular level is considered to be 1 of the major challenges in modern medicine, and it is hoped that QTL discovery in animal models and in humans will reveal mechanistic pathways that can ultimately serve as new targets for therapeutic intervention. The spontaneously hypertensive rat (SHR) and the Dahl salt-sensitive rat are the most widely studied animal models of spontaneous hypertension, and their value for investigating the pharmacology and pathophysiology of hypertension and cardiovascular disease has been recognized for many years. 1-3 Until recently, however, it was unclear whether these spontaneous animal models of hypertension would prove useful for the identification of naturally occurring gene variants involved in the regulation of blood pressure (BP) or related cardiovascular and metabolic phenotypes. It was also unknown whether any such genes would prove relevant to the pathogenesis and treatment of any clinical disorders in humans.Major advances in methods for QTL mapping, together with the pioneering research of Rapp 4 and other investigators, sparked multiple efforts to map genes influencing BP-related phenotypes in Dahl rats and in the SHR. These ...

The stroke-prone spontaneously hypertensive rat: still a useful model for post-GWAS genetic studies?

“…In the following studies on rats and humans, substantial evidence was accumulated supporting the role of Cd36 in hypertension and insulin resistance. 42 On the other hand, it was reported that SHR/Izm, which is a substrain of SHR used in Japan, did not have the Cd36 deletion though it still showed insulin resistance as well as hypertension. 43 This observation indicated that Cd36 did not have a major role in insulin resistance and hypertension in SHR/Izm.…”

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“…Furthermore, there are instances that the rat model has inspired new therapeutic approaches (Gelderman et al 2007, Pravenec & Kurtz 2007. The efficiency of translating results from rat models to the human thus seems to be high and rat model studies should thus provide important insights into disease genetics and mechanisms, as well as new therapeutic approaches.…”

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“…In vertebrates, CD36 is an 88-kDa integral membrane protein receptor that mediates internalization of oxidized low-density lipoprotein by macrophages (16), formation of atherosclerotic plaques (17), and the import of long-chain fatty acids by adipose, heart, and other tissues (18,19). In humans, loss of CD36 is linked to a wide range of disorders including insulin resistance, dyslipidemia, and atherosclerosis (17,18,(20)(21)(22). CD36 molecules share a common domain structure with short intracellular domains at the N and C termini, two membrane spanning domains, and a large extracellular domain (19).…”