Objectives:
The annual mortality in the United States from ruptured aortic aneurysms is ~15000. Therapeutic interventions that prevent AAA progression and rupture remain to be identified. In humans, plasma concentrations of the acute phase reactant serum amyloid A (SAA) correlates with aortic dimensions before aneurysm formation. We have shown that endogenous SAA augments AAA in the well-established angiotensin II (AngII) infusion mouse model (unpublished data). Here we investigated whether endogenous SAA impacts aneurysm formation induced by deoxycorticosterone acetate (DOCA), a mineralocorticoid receptor agonist, in the presence of high salt.
Approach and results:
DOCA pellets (50mg, 21 day release) were implanted subcutaneously in the lateral dorsal region of 8-month old male C57BL/6 (SAAWT) mice and C57BL/6 mice lacking both acute phase SAA isoforms, SAA1.1 and SAA2.1 (SAAKO). The mice were also provided drinking water containing 0.9% NaCl and 0.2% KCl for 21 days (n = 7-8). As expected, DOCA + salt resulted in significantly increased systolic blood pressure, which was not affected by the absence of SAA. Unexpectedly SAAKO mice displayed a reduced urine output, accompanied by a reduced water intake. Plasma sodium and potassium concentrations in SAAWT and SAAKO mice were similar after treatment. The maximal luminal diameter of the abdominal aorta, as determined by ultrasound, was significantly lower in SAAKO mice compared to SAAWT mice after a 3-week DOCA + salt regime. Aneurysm incidence, determined by ultrasound and ex vivo analyses, was 67% for SAAWT mice and 25 % for SAAKO mice. Notably, plasma SAA was markedly increased in the SAAWT mice that formed aneurysms compared to those that did not. In SAAWT mice, immunohistochemical staining and in situ zymography identified SAA in aneurysmal aortic tissue, but not control aortas, that co-localized to regions of enhanced matrix metalloproteinase (MMP) activity, suggesting a role for SAA in MMP activation.
Conclusions:
We conclude that endogenous SAA augments aortic aneurysm formation induced by mineralocorticoid receptor agonists in the presence of high salt. Thus, SAA contributes to pathological processes leading to aortic aneurysm in two robust and mechanistically distinct animal models.
A mathematical model of aortic aneurysm formation
