Inhibition of Marfan Syndrome Aortic Root Dilation by Losartan

Abstract

Marfan syndrome (MFS) is a genetic disorder that frequently leads to aortic root dissection and aneurysm. Despite promising preclinical and pilot clinical data, a recent large-scale study using antihypertensive angiotensin II (AngII) receptor type 1 (ATR1) blocker losartan has failed to meet expectations at preventing MFS-associated aortic root dilation, casting doubts about optimal therapy. To study the deleterious role of normal ATR1 signaling in aortic root widening, we generated MFS mice lacking ATR1a expression in an attempt to preserve protective ATR2 signaling. Despite being hypotensive and resistant to AngII vasopressor effects, MFS/ATR1a-null mice showed unabated aortic root enlargement and remained fully responsive to losartan, confirming that blood pressure lowering is of minor therapeutic value in MFS and that losartan's antiremodeling properties may be ATR1 independent. Having shown that MFS causes endothelial dysfunction and that losartan can activate endothelial function in mice and patients, we found that nitric oxide synthase (NOS) inhibition renders losartan therapeutically inactive, whereas multiple transgenic and pharmacologic models of endothelial NOS activation block aortic root dilation by correcting extracellular signal-regulated kinase signaling. In vitro, losartan can increase endothelial NO release in the absence of AngII and correct MFS NO levels in vivo. Our data suggest that increased protective endothelial function, rather than ATR1 inhibition or blood pressure lowering, might be of therapeutic significance in preventing aortic root disease in MFS.

TGF-β Signaling-Related Genes and Thoracic Aortic Aneurysms and Dissections

“…In MFS patients, endothelial dysfunction and increased aortic stiffness are associated with aortic aneurysmal formation [ 48 , 49 , 50 ], and losartan attenuates impairment of endothelial function in MFS mice and patients ( Figure 3 ). Sellers et al reported that Fbn1 C1039G/+ mice crossed with hypotensive Agt1ar knockout mice ( Fbn1 C1039G/+ : Agt1ar −/− ) showed unabated aortic aneurysmal formation [ 51 ]. However, losartan treatment still had a favorable effect on disease progression, suggesting that losartan’s anti-remodeling properties might be independent of its blood-lowering effect [ 51 ].…”

“…Sellers et al reported that Fbn1 C1039G/+ mice crossed with hypotensive Agt1ar knockout mice ( Fbn1 C1039G/+ : Agt1ar −/− ) showed unabated aortic aneurysmal formation [ 51 ]. However, losartan treatment still had a favorable effect on disease progression, suggesting that losartan’s anti-remodeling properties might be independent of its blood-lowering effect [ 51 ]. In addition, losartan could increase endothelial nitric oxide (NO) release, and it did not ameliorate aneurysmal formation in Fbn1 C1039G/+ mice treated with L-NAME (N omega-nitro-L-arginine methyl ester), a nitric oxide synthase (NOS) inhibitor.…”

“…In addition, losartan could increase endothelial nitric oxide (NO) release, and it did not ameliorate aneurysmal formation in Fbn1 C1039G/+ mice treated with L-NAME (N omega-nitro-L-arginine methyl ester), a nitric oxide synthase (NOS) inhibitor. Furthermore, Fbn1 C1039G/+ mice expressing a constitutively active endothelial NOS mutation [eNOS 1176 Ser-to-Asp knock-in (S1176D)] showed attenuated aortic disease, whereas Fbn1 C1039G/+ mice expressing an inactive form of an eNOS mutation [eNOS 1176 Ser-to-Ala knock-in (S176A)] caused a nonsignificant increase in the aortic diameter [ 51 ]. These data might indicate that losartan’s effect on aortic aneurysmal formation is NO-dependent, and protection of endothelial function might be of therapeutic significance to prevent aortic aneurysmal formation.…”

Anatomically specific reactive oxygen species production participates in Marfan syndrome aneurysm formation

“…Finally, we cannot rule out that AngII participates in aneurysm formation through an alternative mechanism, for example direct stimulation of MMP activation . It is intriguing that the protective clinical benefit of losartan noted in several MFS clinical trials may be secondary to blockade of AngII‐stimulated ROS production …”

“…58,59 It is intriguing that the protective clinical benefit of losartan noted in several MFS clinical trials may be secondary to blockade of AngII-stimulated ROS production. [60][61][62][63][64][65][66][67][68][69][70]…”