Elevated Adiponectin Levels Suppress Perivascular and Aortic Inflammation and Prevent AngII-induced Advanced Abdominal Aortic Aneurysms

Abstract

Abdominal aortic aneurysm (AAA) is a degenerative disease characterized by aortic dilation and rupture leading to sudden death. Currently, no non-surgical treatments are available and novel therapeutic targets are needed to prevent AAA. We investigated whether increasing plasma levels of adiponectin (APN), a pleiotropic adipokine, provides therapeutic benefit to prevent AngII-induced advanced AAA in a well-established preclinical model. In the AngII-infused hyperlipidemic low-density lipoprotein receptor-deficient mouse (LDLR−/−) model, we induced plasma APN levels using a recombinant adenovirus expressing mouse APN (AdAPN) and as control, adenovirus expressing green florescent protein (AdGFP). APN expression produced sustained and significant elevation of total and high-molecular weight APN levels and enhanced APN localization in the artery wall. AngII infusion for 8 weeks induced advanced AAA development in AdGFP mice. Remarkably, APN inhibited the AAA development in AdAPN mice by suppressing aortic inflammatory cell infiltration, medial degeneration and elastin fragmentation. APN inhibited the angiotensin type-1 receptor (AT1R), inflammatory cytokine and mast cell protease expression, and induced lysyl oxidase (LOX) in the aortic wall, improved systemic cytokine profile and attenuated adipose inflammation. These studies strongly support APN therapeutic actions through multiple mechanisms inhibiting AngII-induced AAA and increasing plasma APN levels as a strategy to prevent advanced AAA.

ADAMTS-1 in abdominal aortic aneurysm

“…Sections were then stained for collagen and elastin as previously described [13]. Sections were studied under light microscopy ZEN 2012 (Zeiss, Jena, Germany).…”

“…Paraffin-embedded sections (5 μm) from mice aorta were rehydrated in several changes of ethanol and Tissue-Clear ® (Sakura Finetek). Sections were then stained for collagen and elastin as previously described [ 13 ]. Sections were studied under light microscopy ZEN 2012 (Zeiss, Jena, Germany).…”

Alcohol consumption and mortality from aortic disease among Japanese men: The Japan Collaborative Cohort study

“…Light to moderate alcohol consumption has been associated with lower levels of inflammation markers including interleukin-6 (an upstream maker of C-reactive protein or fibrinogen) [20,21], whose receptor is an important pathway for the development of abdominal aortic aneurysm [22]. Furthermore, moderate alcohol consumption reduced platelet aggregation [23] and circulating MMP-2 activity [24], enhanced fibrinolysis [25], and increased adiponectin level [18], all of which contribute to the reduced risk of aortic diseases [26][27][28] . Although the causality cannot be determined from an observational study, our findings could be generalized to middle-aged men of other ethnicities according to these mechanisms.…”

Role of Adipokines and Perivascular Adipose Tissue in Abdominal Aortic Aneurysm: A Systematic Review and Meta-Analysis of Animal and Human Observational Studies

“…Ten eligible rodent studies were identified (19)(20)(21)(22)(23)(24)(25)(26)(27)(28). These studies included a total of 319 rodents in which the effects of leptin, resistin, adiponectin, and PVAT were investigated (19)(20)(21)(22)(23)(24)(25)(26)(27)(28). Detailed information about each study is shown in Table 1.…”