Adipocyte-Derived Serum Amyloid A Promotes Angiotensin II–Induced Abdominal Aortic Aneurysms in Obese C57BL/6J Mice

Abstract

Background: Obesity increases the risk for human abdominal aortic aneurysms (AAAs) and enhances Ang II (angiotensin II)–induced AAA formation in C57BL/6J mice. Obesity is also associated with increases in perivascular fat that expresses proinflammatory markers including SAA (serum amyloid A). We previously reported that deficiency of SAA significantly reduces Ang II–induced inflammation and AAA in hyperlipidemic apoE-deficient mice. In this study. we investigated whether adipose tissue-derived SAA plays a role in Ang II–induced AAA in obese C57BL/6J mice. Methods: The development of AAA was compared between male C57BL/6J mice (wild type), C57BL/6J mice lacking SAA1.1, SAA2.1, and SAA3 (TKO); and TKO mice harboring a doxycycline-inducible, adipocyte-specific SAA1.1 transgene (TKO-Tg fat ; SAA expressed only in fat). All mice were fed an obesogenic diet and doxycycline to induce SAA transgene expression and infused with Ang II to induce AAA. Results: In response to Ang II infusion, SAA expression was significantly increased in perivascular fat of obese C57BL/6J mice. Maximal luminal diameters of the abdominal aorta were determined by ultrasound before and after Ang II infusion, which indicated a significant increase in aortic luminal diameters in wild type and TKO-TG fat mice but not in TKO mice. Adipocyte-specific SAA expression was associated with MMP (matrix metalloproteinase) activity and macrophage infiltration in abdominal aortas of Ang II–infused obese mice. Conclusions: We demonstrate for the first time that SAA deficiency protects obese C57BL/6J mice from Ang II–induced AAA. SAA expression only in adipocytes is sufficient to cause AAA in obese mice infused with Ang II.

Antisense Oligonucleotide Targeting Hepatic Serum Amyloid A Limits the Progression of Angiotensin II-Induced Abdominal Aortic Aneurysm Formation

“…The current study expands on results from our previous reports that SAA is essential for the development of AngII-induced AAA formation in both hyperlipidemic apoE -/-15 and obese C57BL/6 mice 16 . In the current study, we investigated the protective effect of an antisense oligonucleotide inhibitor of SAA synthesis on the progression of early AngIIinduced AAAs 13 in obese C57BL/6 mice.…”

“…Mice that did not meet the 25% increase in luminal diameter after 4 weeks of AngII compared to the respective baseline diameters were dropped from the study, and the data generated from these mice are excluded from further analysis. SAA ASO administration significantly suppressed plasma SAA levels and liver SAA1.1 and SAA2.1 expression HFD feeding and AngII infusion increases plasma SAA levels in mice 15,16 . As expected, intraperitoneal (i.p.)…”

“…HFD feeding and AngII infusion increases plasma SAA levels in mice 15,16 . As expected, intraperitoneal ( i.p. )…”

“…Obesity increases the risk for human AAAs 22 and enhances AngII-induced AAA formation in C57BL/6 mice 14 . Both obesity and AngII treatment increase systemic SAA levels in mice 16 . The liver is thought to be the primary source of circulating SAA in mice following AngII infusion.…”

“…Our group reported the key finding that deficiency of SAA in hyperlipidemic apolipoprotein E-deficient (apoE -/- ) mice significantly reduces AngII-induced AAA 15 . Recently, we also reported that SAA exacerbates AAA development in obese mice infused with AngII 16 . In the present study, we investigated whether antisense-oligonucleotide (ASO)-mediated inhibition of SAA protects mice from the progression of an early AAA.…”