Evolving concepts of the renin-angiotensin system: Highlights from the pre-ISH 2012 satellite meeting

摘要

Despite its long history, the renin-angiotensin system remains an active area of research. New components and interactions between novel and established components continue to be discovered. These developments are providing fresh insight into the role of the renin-angiotensin system in cardiovascular health and disease and new therapeutic targets for the prevention and treatment of cardiovascular disease. The pre-ISH 2012 satellite ‘Evolving concepts of the renin-angiotensin system’ provided a timely opportunity to review progress and to discuss the future of this exciting and productive area of research. The pre-ISH 2012 satellite meeting ‘Evolving concepts of the renin-angiotensin system’ (RAS) took place at Cypress Lakes, Hunter Valley, Australia, on 26–28 September 2012. The satellite meeting attracted more than 60 participants and brought together many leading national and international RAS experts. Delegates soaked up the latest opinions, trends and insights and honed new ideas relating to the RAS. Although the RAS was discovered more than 100 years ago, new components of the RAS and new interactions between RAS components continue to be discovered. The following report reviews the key messages that came out of the highly interactive discussions at the meeting. These included exciting new insights into the role of the RAS in cardiovascular health and disease, and the identification of new therapeutic targets. Previous SectionNext Section Clinical aspects Michael Stowasser reviewed the clinical rationale for detection and treatment of primary aldosteronism and described the utility of aldosterone measurement by mass spectrometry. Subsequently, Marko Poglitsch described the use of mass spectrometry to measure angiotensin (Ang) peptides and their metabolites in plasma. Jan Danser reviewed the current and possible future clinical role of renin inhibition. Combination of the renin inhibitor aliskiren with either angiotensin-converting enzyme (ACE) inhibitor or angiotensin type 1 (AT1) receptor blocker (ARB) therapy in diabetic patients with renal impairment (ALTITUDE study) failed to produce benefit. However, study of the combination in heart failure patients (ATMOSPHERE study) is ongoing. Suang Suang Koid described the reduction of myocardial ischemia-reperfusion injury in rats treated with aliskiren. These studies were based on the observation that aliskiren increases myocardial bradykinin levels by an off-target mechanism independent of renin inhibition. The cardioprotective effects of aliskiren were prevented by the bradykinin type 2 (B2) receptor antagonist icatibant. These studies suggest that aliskiren may produce cardiovascular benefits beyond blood pressure control. Previous SectionNext Section AT2 and Mas receptors, ACE2 and Ang-(1-7) A key theme of the meeting extending across several sessions was the role and interaction between the components of the cardioprotective arm of the RAS, comprising the Ang II type 2 (AT2) and Ang-(1-7) (Mas) receptors, ACE2 and Ang-(1-7). Michael Bader described Mas receptor gene knockout mice with a phenotype of increased cardiovascular disease risk, including increased blood pressure, fat mass, and plasma cholesterol and triglyceride levels. Conversely, transgenic rats with increased expression of Ang-(1-7) had an improved metabolic profile with enhanced glucose tolerance, insulin sensitivity, and insulin-stimulated glucose uptake, decreased triglyceride and cholesterol levels, and a significant decrease in abdominal fat mass, despite normal food intake, whereas circulating insulin and muscle glycogen content were not altered. Moreover, treatment of diabetic rats with an oral (hydroxypropyl-?-cyclodextrin-based) Ang-(1-7) formulation improved insulin action and ameliorated hyperglycemia. Evidence for a cardioprotective role for ACE2 was provided by transgenic spontaneously hypertensive stroke-prone rats (SHRSP) with over-expression of the ACE2 gene in vascular smooth muscle. In compa