Deficiency of Endogenous Acute-Phase Serum Amyloid A Protects apoE-/- Mice From Angiotensin II-Induced Abdominal Aortic Aneurysm Formation.
OBJECTIVE
Rupture of abdominal aortic aneurysm (AAA), a major cause of death in the aged population, is characterized by vascular inflammation and matrix degradation. Serum amyloid A (SAA), an acute-phase reactant linked to inflammation and matrix metalloproteinase induction, correlates with aortic dimensions before aneurysm formation in humans. We investigated whether SAA deficiency in mice affects AAA formation during angiotensin II (Ang II) infusion.


RESULTS
Plasma SAA increased ≈60-fold in apoE(-/-) mice 24 hours after intraperitoneal Ang II injection (100 μg/kg; n=4) and ≈15-fold after chronic 28-day Ang II infusion (1000 ng/kg per minute; n=9). AAA incidence and severity after 28-day Ang II infusion was significantly reduced in apoE(-/-) mice lacking both acute-phase SAA isoforms (SAAKO; n=20) compared with apoE(-/-) mice (SAAWT; n=20) as assessed by in vivo ultrasound and ex vivo morphometric analyses, despite a significant increase in systolic blood pressure in SAAKO mice compared with SAAWT mice after Ang II infusion. Atherosclerotic lesion area of the aortic arch was similar in SAAKO and SAAWT mice after 28-day Ang II infusion. Immunostaining detected SAA in AAA tissues of Ang II-infused SAAWT mice that colocalized with macrophages, elastin breaks, and enhanced matrix metalloproteinase activity. Matrix metalloproteinase-2 activity was significantly lower in aortas of SAAKO mice compared with SAAWT mice after 10-day Ang II infusion.


CONCLUSIONS
Lack of endogenous acute-phase SAA protects against experimental AAA through a mechanism that may involve reduced matrix metalloproteinase-2 activity.
From the Departments of Pharmacology Division of Nutritional Sciences (N.R.W.), Physiology (M.C.D.B.) and Internal Medicine (J.M.W., A.J., W.B., P.S., V.P.N., D.A.H., A.B., D.L.R., A.D., F.C.D.B.), and Saha Cardiovascular Research Center (N.R.W., M.C.D.B., J.M.W., A.J., P.S., V.P.N., D.A.H., A.B., D.L.R., A.D., F.C.D.B.), and Departments of Statistics and Biostatistics (R.J.C.), University of Kentucky, Lexington; and Foundation Gastroenterology, Nashua, NH (J.W.). nrwebb1@uky.edu.
Nancy R
NR
Webb
From the Departments of Pharmacology Division of Nutritional Sciences (N.R.W.), Physiology (M.C.D.B.) and Internal Medicine (J.M.W., A.J., W.B., P.S., V.P.N., D.A.H., A.B., D.L.R., A.D., F.C.D.B.), and Saha Cardiovascular Research Center (N.R.W., M.C.D.B., J.M.W., A.J., P.S., V.P.N., D.A.H., A.B., D.L.R., A.D., F.C.D.B.), and Departments of Statistics and Biostatistics (R.J.C.), University of Kentucky, Lexington; and Foundation Gastroenterology, Nashua, NH (J.W.).
Maria C
MC
De Beer
From the Departments of Pharmacology Division of Nutritional Sciences (N.R.W.), Physiology (M.C.D.B.) and Internal Medicine (J.M.W., A.J., W.B., P.S., V.P.N., D.A.H., A.B., D.L.R., A.D., F.C.D.B.), and Saha Cardiovascular Research Center (N.R.W., M.C.D.B., J.M.W., A.J., P.S., V.P.N., D.A.H., A.B., D.L.R., A.D., F.C.D.B.), and Departments of Statistics and Biostatistics (R.J.C.), University of Kentucky, Lexington; and Foundation Gastroenterology, Nashua, NH (J.W.).
Joanne M
JM
Wroblewski
From the Departments of Pharmacology Division of Nutritional Sciences (N.R.W.), Physiology (M.C.D.B.) and Internal Medicine (J.M.W., A.J., W.B., P.S., V.P.N., D.A.H., A.B., D.L.R., A.D., F.C.D.B.), and Saha Cardiovascular Research Center (N.R.W., M.C.D.B., J.M.W., A.J., P.S., V.P.N., D.A.H., A.B., D.L.R., A.D., F.C.D.B.), and Departments of Statistics and Biostatistics (R.J.C.), University of Kentucky, Lexington; and Foundation Gastroenterology, Nashua, NH (J.W.).
Ailing
A
Ji
From the Departments of Pharmacology Division of Nutritional Sciences (N.R.W.), Physiology (M.C.D.B.) and Internal Medicine (J.M.W., A.J., W.B., P.S., V.P.N., D.A.H., A.B., D.L.R., A.D., F.C.D.B.), and Saha Cardiovascular Research Center (N.R.W., M.C.D.B., J.M.W., A.J., P.S., V.P.N., D.A.H., A.B., D.L.R., A.D., F.C.D.B.), and Departments of Statistics and Biostatistics (R.J.C.), University of Kentucky, Lexington; and Foundation Gastroenterology, Nashua, NH (J.W.).
William
W
Bailey
From the Departments of Pharmacology Division of Nutritional Sciences (N.R.W.), Physiology (M.C.D.B.) and Internal Medicine (J.M.W., A.J., W.B., P.S., V.P.N., D.A.H., A.B., D.L.R., A.D., F.C.D.B.), and Saha Cardiovascular Research Center (N.R.W., M.C.D.B., J.M.W., A.J., P.S., V.P.N., D.A.H., A.B., D.L.R., A.D., F.C.D.B.), and Departments of Statistics and Biostatistics (R.J.C.), University of Kentucky, Lexington; and Foundation Gastroenterology, Nashua, NH (J.W.).
Preetha
P
Shridas
From the Departments of Pharmacology Division of Nutritional Sciences (N.R.W.), Physiology (M.C.D.B.) and Internal Medicine (J.M.W., A.J., W.B., P.S., V.P.N., D.A.H., A.B., D.L.R., A.D., F.C.D.B.), and Saha Cardiovascular Research Center (N.R.W., M.C.D.B., J.M.W., A.J., P.S., V.P.N., D.A.H., A.B., D.L.R., A.D., F.C.D.B.), and Departments of Statistics and Biostatistics (R.J.C.), University of Kentucky, Lexington; and Foundation Gastroenterology, Nashua, NH (J.W.).
Richard J
RJ
Charnigo
From the Departments of Pharmacology Division of Nutritional Sciences (N.R.W.), Physiology (M.C.D.B.) and Internal Medicine (J.M.W., A.J., W.B., P.S., V.P.N., D.A.H., A.B., D.L.R., A.D., F.C.D.B.), and Saha Cardiovascular Research Center (N.R.W., M.C.D.B., J.M.W., A.J., P.S., V.P.N., D.A.H., A.B., D.L.R., A.D., F.C.D.B.), and Departments of Statistics and Biostatistics (R.J.C.), University of Kentucky, Lexington; and Foundation Gastroenterology, Nashua, NH (J.W.).
Victoria P
VP
Noffsinger
From the Departments of Pharmacology Division of Nutritional Sciences (N.R.W.), Physiology (M.C.D.B.) and Internal Medicine (J.M.W., A.J., W.B., P.S., V.P.N., D.A.H., A.B., D.L.R., A.D., F.C.D.B.), and Saha Cardiovascular Research Center (N.R.W., M.C.D.B., J.M.W., A.J., P.S., V.P.N., D.A.H., A.B., D.L.R., A.D., F.C.D.B.), and Departments of Statistics and Biostatistics (R.J.C.), University of Kentucky, Lexington; and Foundation Gastroenterology, Nashua, NH (J.W.).
Jassir
J
Witta
From the Departments of Pharmacology Division of Nutritional Sciences (N.R.W.), Physiology (M.C.D.B.) and Internal Medicine (J.M.W., A.J., W.B., P.S., V.P.N., D.A.H., A.B., D.L.R., A.D., F.C.D.B.), and Saha Cardiovascular Research Center (N.R.W., M.C.D.B., J.M.W., A.J., P.S., V.P.N., D.A.H., A.B., D.L.R., A.D., F.C.D.B.), and Departments of Statistics and Biostatistics (R.J.C.), University of Kentucky, Lexington; and Foundation Gastroenterology, Nashua, NH (J.W.).
Deborah A
DA
Howatt
From the Departments of Pharmacology Division of Nutritional Sciences (N.R.W.), Physiology (M.C.D.B.) and Internal Medicine (J.M.W., A.J., W.B., P.S., V.P.N., D.A.H., A.B., D.L.R., A.D., F.C.D.B.), and Saha Cardiovascular Research Center (N.R.W., M.C.D.B., J.M.W., A.J., P.S., V.P.N., D.A.H., A.B., D.L.R., A.D., F.C.D.B.), and Departments of Statistics and Biostatistics (R.J.C.), University of Kentucky, Lexington; and Foundation Gastroenterology, Nashua, NH (J.W.).
Anju
A
Balakrishnan
From the Departments of Pharmacology Division of Nutritional Sciences (N.R.W.), Physiology (M.C.D.B.) and Internal Medicine (J.M.W., A.J., W.B., P.S., V.P.N., D.A.H., A.B., D.L.R., A.D., F.C.D.B.), and Saha Cardiovascular Research Center (N.R.W., M.C.D.B., J.M.W., A.J., P.S., V.P.N., D.A.H., A.B., D.L.R., A.D., F.C.D.B.), and Departments of Statistics and Biostatistics (R.J.C.), University of Kentucky, Lexington; and Foundation Gastroenterology, Nashua, NH (J.W.).
Debra L
DL
Rateri
From the Departments of Pharmacology Division of Nutritional Sciences (N.R.W.), Physiology (M.C.D.B.) and Internal Medicine (J.M.W., A.J., W.B., P.S., V.P.N., D.A.H., A.B., D.L.R., A.D., F.C.D.B.), and Saha Cardiovascular Research Center (N.R.W., M.C.D.B., J.M.W., A.J., P.S., V.P.N., D.A.H., A.B., D.L.R., A.D., F.C.D.B.), and Departments of Statistics and Biostatistics (R.J.C.), University of Kentucky, Lexington; and Foundation Gastroenterology, Nashua, NH (J.W.).
Alan
A
Daugherty
From the Departments of Pharmacology Division of Nutritional Sciences (N.R.W.), Physiology (M.C.D.B.) and Internal Medicine (J.M.W., A.J., W.B., P.S., V.P.N., D.A.H., A.B., D.L.R., A.D., F.C.D.B.), and Saha Cardiovascular Research Center (N.R.W., M.C.D.B., J.M.W., A.J., P.S., V.P.N., D.A.H., A.B., D.L.R., A.D., F.C.D.B.), and Departments of Statistics and Biostatistics (R.J.C.), University of Kentucky, Lexington; and Foundation Gastroenterology, Nashua, NH (J.W.).
Frederick C
FC
De Beer
D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D017544:Aortic Aneurysm, Abdominal / Q000473:pathology / Q000517:prevention & control*; D001057:Apolipoproteins E / Q000172:deficiency*; D015415:Biomarkers / Q000097:blood; D004195:Disease Models, Animal; D004549:Elastin / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011897:Random Allocation; D012680:Sensitivity and Specificity; D000685:Serum Amyloid A Protein / Q000172:deficiency* / Q000378:metabolism
D001057:Apolipoproteins E; D015415:Biomarkers; D000685:Serum Amyloid A Protein; D000804:Angiotensin II; D004549:Elastin; D020778:Matrix Metalloproteinase 2
acute-phase proteins; aneurysm; inflammation; serum amyloid A protein