Editorial [ Hot Topic : Inhibition of the Renin-Angiotensin-Aldosterone System: How to Obtain This (Executive Guest Editors: Aldo Pende and Fabrizio Montecucco )]

The renin-angiotensin-aldosterone system (RAAS) exerts a crucial role in the regulation of blood pressure and its pharmacological inhibition is essential to prevent cardiovascular events related to hypertension [1]. This “historical” concept has been recently updated by several knowledge improvements, suggesting that the RAAS might induce a series of “pleiotropic activities” [2]. This system has been shown to trigger intracellular cascades via selective transmembrane receptors in several cell subsets and peripheral tissues [2]. Furthermore, the recent identification of an “intracellular” Renin-Angiotensin System (RAS) has further increased the complexity of the classical hormonal axis. The strong effort of experimental and clinical researches have also highlighted new peptides (such as Angiotensins), receptors and enzymes [3] that might directly regulate inflammatory mechanisms in aging [4]. On the basis of these discoveries, both systemic and intracellular RAS have been investigated to better understand their role in different diseases, such as atherosclerosis and related inflammation. In addition, these studies have contributed to better define novel therapeutic targets and beneficial effects for drugs inhibiting RAAS. Several efficient inhibitory drugs (such as angiotensin-converting enzyme inhibitors [ACEIs], angiotensin II type 1 receptor blockers [ARBs], aldosterone antagonists, and renin inhibitors) have been shown to directly reduce inflammatory and vascular cell activation [5, 6]. Given this emerging background, the present Hot-Topic Issue will update the pleiotropic activities of RAAS and the different strategies targeting its inhibition. Veglio and co-workers discussed the rationale and the possible use of different combinations among RAAS antagonists in certain diseases, such as heart failure, proteinuric nephropathy, and resistant hypertension. Although it should be carefully monitored for safety concerns, an approach characterized by a more complete blockade of the system using RAAS blockers' combinations could be recommended. Stohr and Marx focused on the potential benefits of treatments with RAAS blockers in the prevention of type 2 diabetes mellitus. In their review, authors updated evidence on the contrasting metabolic effects of RAAS inhibitors in humans and mice. Capettini and co-workers discussed on the interesting interactions between RAAS and immunological aspects in aging. RAAS has been shown to modulate the production of reactive oxygen species (ROS) and the release of inflammatory mediators (such as certain cytokines and chemokines), thus potentially regulating the immune response in inflammatory disorders. In particular, the possible role of the counterbalancing anti-inflammatory ACE2/Ang-(1-7)/Mas receptor axis has been updated.