Cardiovascular disease will be the number one health care burden of the 21st century, and is predicted to be the most common cause of death worldwide by 2020. A major risk factor for heart disease is high blood pressure. Hypertension is a multifactorial quantitative trait controlled by both genetic and environmental factors. While much is known about environmental factors that can contribute to high blood pressure, such as diet and physical activity, less is known about the genetic factors that are responsible for predisposition to cardiovascular disease. Despite the identification of several putative genetic quantitative trait loci (QTL) associated with hypertension in animal models, none of these loci have been translated into genes. Thus, the molecular and genetic mechanisms underlying hypertension and other cardiovascular diseases remain largely obscure.
One critical regulator of blood pressure homeostasis is the renin-angiotensin system (RAS). The protease renin cleaves angiotensinogen into the inactive decameric peptide angiotensin I (AngI). The action of angiotensin-converting enzyme (ACE) then catalyzes the cleavage of the AngI into the active octomer angiotensin II (AngII), which can contribute to hypertension by promoting vascular smooth muscle vasoconstriction and renal tubule sodium reabsorption. ACE mutant mice display spontaneous hypotension, partial male infertility, and kidney malformations. In humans, an ACE polymorphism has been associated with determinants of renal and cardiovascular function, and pharmacological inhibition of ACE and AngII receptors are effective in lowering blood pressure and kidney disease. In addition, inhibition of ACE and AngII receptors has beneficial effects in heart failure.
Recently a homologue of ACE, termed ACE2, has been identified which is predominantly expressed in the vascular endothelial cells of the kidney and heart. Interestingly, two ACE homologues also exist in flies. Unlike ACE, ACE2 functions as a carboxypeptidase, cleaving a single residue from AngI, generating Ang1-9, and a single residue form AngII to generate Ang1-7. These in vitro biochemical data suggested that, ACE2 modulates the RAS and thus may play a role in blood pressure regulation. The in vivo role of ACE2 in the cardiovascular system and the RAS is not known.
Acton et al. in U.S. Pat. No. 6,194,556, describe the use of ACE2 in diagnosis and therapeutics of ACE2 associated states. The patent stated that ACE2 expression levels increase with hypertension and that antagonists or inhibitors of ACE2 activity would be useful in the treatment of increased blood pressure or related disorders. Canadian patent application no. 2,372,387 provides specific examples of ACE2 inhibitors which, are intended to be useful for the treatment of heart disease, such as hypertension. This again emphasizes the need to inhibit, rather than increase, ACE2 activity. These references, which teach the need to inhibit ACE2 activity, are based only on in vitro experimental data. They do not provide in vivo data, such as knock out mammal data, to characterize ACE2. To date, no ACE2 inhibitors have been approved as pharmaceuticals for treatment of hypertension. Furthermore, the in vivo role of ACE2 in the cardiovascular system and the RAS remains largely unknown. There remains a need to characterize the function of ACE2 in order to be able to design appropriate diagnostic tests and pharmaceuticals for treatment of heart and kidney disease.
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