Aortic Pathology and the Role of the Renin-Angiotensin System

Thoracic aortic aneurysms (TAAs) are a potential life-threatening disease with limited pharmacological treatment options. Current treatment options are aimed at lowering aortic hemodynamic stress, predominantly with beta-blockers. Increasing evidence supports a role for the renin-angiotensin system (RAS) in aneurysm development. RAS blockade would not only lower blood pressure, but might also target the molecular pathways involved in aneurysm formation, in particular the transforming growth factor-beta (TGF-β)- and extracellular signalregulated kinase (ERK) 1/2 pathways. Indeed, the angiotensin II type 1 (AT1) receptor blocker losartan was effective in lowering aortic root growth in mice and patients with Marfan syndrome. RAS inhibition, which is currently possible at three levels (renin, ACE and the AT1 receptor), is always accompanied by a rise in renin due to interference with the negative feedback loop between renin and angiotensin II. Only during AT1 receptor blockade will this result in stimulation of the non-blocked angiotensin II type 2 (AT2) receptor. This review summarizes the clinical aspects of TAAs, provides an overview of the current mouse models for TAAs, and focuses on the RAS as a new target for TAA treatment, discussing in particular the possibility that AT2 receptor stimulation might be crucial in this regard. If true, this would imply that AT1 receptor blockers (and not ACE inhibitors or renin inhibitors) should be the preferred treatment option for TAAs

The chemical composition of globular clusters in the Local Group

We present detailed abundance measurements for 45 globular clusters (GCs) in galaxies in (and, in one case, beyond) the Local Group. The measurements are based on new high-resolution integrated-light spectra of GCs in NGC 185, NGC 205, M31, M33, and NGC 2403, combined with reanalysis of previous observations of GCs in the Fornax dSph, WLM, NGC 147, NGC 6822, and the Milky Way. The GCs cover the range -2.8 < [Fe/H] < -0.1 and we determined abundances for Fe, Na, Mg, Si, Ca, Sc, Ti, Cr, Mn, Ni, Cu, Zn, Zr, Ba, and Eu. Corrections for non local thermodynamic equilibrium effects are included for Na, Mg, Ca, Ti, Mn, Fe, Ni, and Ba. For several of the galaxies, our measurements provide the first quantitative constraints on the detailed composition of their metal-poor stellar populations. Overall, the GCs in different galaxies exhibit remarkably uniform abundance patterns of the alpha-, iron-peak, and neutron-capture elements, with a dispersion of less than 0.1 dex in [alpha/Fe] for the full sample. There is a hint that GCs in dwarf galaxies are slightly less alpha-enhanced (by about 0.04 dex on average) than those in larger galaxies. One GC in M33 (HM33-B) resembles the most metal-rich GCs in the Fornax dSph (Fornax 4) and NGC 6822 (SC7) by having alpha-element abundances closer to scaled-solar values, possibly hinting at an accretion origin. We find that the alpha-element abundances strongly correlate with those of Na, Sc, Ni, and Zn. Several GCs with [Fe/H]<-1.5 are deficient in Mg compared to other alpha-elements. We find no GCs with strongly enhanced r-process abundances as reported for metal-poor stars in some ultra-faint dwarfs and the Magellanic Clouds. The similarity of the abundance patterns for metal-poor GCs in different environments points to similar early enrichment histories and only allow for minor variations in the initial mass function.Comment: 34 pages + 6 appendices. Accepted for publication in Astronomy & Astrophysic

Impaired Vascular Contractility and Aortic Wall Degeneration in Fibulin-4 Deficient Mice: Effect of Angiotensin II Type 1 (AT1) Receptor Blockade

Medial degeneration is a key feature of aneurysm disease and aortic dissection. In a murine aneurysm model we investigated the structural and functional characteristics of aortic wall degeneration in adult fibulin-4 deficient mice and the potential therapeutic role of the angiotensin (Ang) II type 1 (AT1) receptor antagonist losartan in preventing aortic media degeneration. Adult mice with 2-fold (heterozygous Fibulin-4+/R) and 4-fold (homozygous Fibulin-4R/R) reduced expression of fibulin-4 displayed the histological features of cystic media degeneration as found in patients with aneurysm or dissection, including elastin fiber fragmentation, loss of smooth muscle cells, and deposition of ground substance in the extracellular matrix of the aortic media. The aortic contractile capacity, determined by isometric force measurements, was diminished, and was associated with dysregulation of contractile genes as shown by aortic transcriptome analysis. These structural and functional alterations were accompanied by upregulation of TGF-β signaling in aortas from fibulin-4 deficient mice, as identified by genome-scaled network analysis as well as by immunohistochemical staining for phosphorylated Smad2, an intracellular mediator of TGF-β. Tissue levels of Ang II, a regulator of TGF-β signaling, were increased. Prenatal treatment with the AT1 receptor antagonist losartan, which blunts TGF-β signaling, prevented elastic fiber fragmentation in the aortic media of newborn Fibulin-4R/R mice. Postnatal losartan treatment reduced haemodynamic stress and improved lifespan of homozygous knockdown fibulin-4 animals, but did not affect aortic vessel wall structure. In conclusion, the AT1 receptor blocker losartan can prevent aortic media degeneration in a non-Marfan syndrome aneurysm mouse model. In established aortic aneurysms, losartan does not affect aortic architecture, but does improve survival. These findings may extend the potential therapeutic application of inhibitors of the renin-angiotensin system to the preventive treatment of aneurysm disease

Levensbericht van W.J.A. Jonckbloet /

Overdruk uit Jaarboek der Koninklijke Akademie van Wetenschappen. - 1886