Statins exert differential effects on angiotensin II-induced atherosclerosis, but no benefit for abdominal aortic aneurysms

Wang, Jianan; Chen, Wen-ai; Wang, Yifan; Zhang, Songzhao; Bi, Honghao; Hong, Bo; Luo, Yueqiu; Daugherty, Alan; Xie, Xing

doi:10.1016/j.atherosclerosis.2011.03.005

Cited by 25 publications

(33 citation statements)

References 28 publications

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“…The differential effect of SAA deficiency on AngII-induced AAA versus AngII-induced atherosclerosis is in agreement with previous studies demonstrating that AAA and atherosclerosis represent rather distinct pathologies that are driven by separate mechanisms 49–52 . We previously reported that deficiency of SAA does not alter atherosclerotic lipid deposition in apoE −/− mice fed either a normal rodent diet for 50 weeks or an atherosclerotic diet for 12 weeks 34 .…”

Section: Discussionsupporting

confidence: 92%

Deficiency of Endogenous Acute-Phase Serum Amyloid A Protects apoE ^−/− Mice From Angiotensin II–Induced Abdominal Aortic Aneurysm Formation

Webb

Beer

Wroblewski

et al. 2015

ATVB

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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. Approach and 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. Webb et al Serum Amyloid A Augments Abdominal Aortic Aneurysm 1157(MMPs) are thought to be intimately involved. 14 There is no proven medical therapy for AAA, with management of patients relying on routine monitoring of AAA size by ultrasound until surgical repair is implemented when the growth rate exceeds 10 mm/y or the diameter exceeds 55 mm.Although the physiological function(s) of SAA have not been clearly established, several studies link SAA with inflammatory processes implicated in AAA formation and progression, such as leukocyte chemotaxis, 15 induction of inflammatory cytokines, [16][17][18] and upregulation of genes involved in extracellular matrix remodeling, including transforming growth factor-β (TGF-β) 19 and MMP expression. 20-23To investigate the possibility that SAA plays a role in the initiation or progression of AAA, mice lacking both acute-phase SAA isoforms 24 were bred into a C57BL/6 background and then crossed with apoE −/− mice, which allowed us to take advantage of the widely used AAA model that involves infusing angiotensin II (Ang II) into hypercholesterolemic mice. Ang II-induced AAAs exhibit many features of human AAA, including medial degeneration, inflammation, thrombus formation, and rupture of the abdominal aorta. 25 Our results demonstrate that SAA augments MMP activity in the abdominal aorta and enhances AAA expansion in Ang II-infused apoE −/− mice. Materials and Meth...

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Section: Discussionsupporting

confidence: 92%

Deficiency of Endogenous Acute-Phase Serum Amyloid A Protects apoE ^−/− Mice From Angiotensin II–Induced Abdominal Aortic Aneurysm Formation

Webb

Beer

Wroblewski

et al. 2015

ATVB

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“…However, we also do not consider it as the major underlying mechanism of CYP2J2 overexpression to attenuate Ang II-induced AAA progression. Research of statins in the Ang II-induced AAA model led to contradictory results (36)(37)(38), but it is sure that the protective effects of statins on AAA are independent of lipid lowering ( 36 ). In addition, HDL and LDL levels are more sensitive predictors of AAA than total cholesterol level ( 39 ), whereas rAAV-CYP2J2 treatment had no signifi cant infl uence on these parameters in the present study.…”

Section: Discussioncontrasting

confidence: 48%

CYP2J2 overexpression increases EETs and protects against angiotensin II-induced abdominal aortic aneurysm in mice

Cai

Zhao

Yan

et al. 2013

Journal of Lipid Research

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Abdominal aortic aneurysms (AAAs) mostly occur in humans over 65 years old ( 1, 2 ). The most dreaded complication of AAA is rupture, and it is the 13th leading cause of death in the United States ( 1 ). At the present time, there is no effi cacious pharmacological therapy, and the surgical treatments carry a high mortality ( 2 ). In the past decades, many studies supported the view that infl ammation played an essential role in the pathogenesis of the disease ( 2-4 ).Cytochrome P450 epoxygenase 2J2 (CYP2J2), which is of human origin and mainly expressed in the cardiovascular system, metabolizes arachidonic acids to epoxyeicosatrienoic acids (EETs) ( 5 ). EETs possess diverse biological functions, and observations reveal that EETs exert protective effects on various cardiovascular diseases, including attenuation of heart injuries and anti-hypertension ( 6-13 ). Recently, Zhang et al. ( 5,14 ) reported that administration of soluble epoxide hydrolase (s-EH) inhibitor, which prevents EET hydration, could prevent angiotensin (Ang) II-induced AAA in mice. However, the underlying mechanisms by which EETs exert the effect and whether increased circulation of EETs by CYP2J2 overexpression could prevent AAA formation remain unknown .EETs are the ligands of peroxisome proliferator-activated receptor (PPAR) ␥ and exert anti-infl ammatory effects ( 15 ). Jones et al. ( 16 ) recently reported that activation of PPAR ␥ byAbstract Cytochrome P450 epoxygenase 2J2 (CYP2J2) metabolizes arachidonic acids to form epoxyeicosatrienoic acids (EETs), which possess various benefi cial effects on the cardiovascular system. However, whether increasing EETs production by CYP2J2 overexpression in vivo could prevent abdominal aortic aneurysm (AAA) remains unknown. Here we investigated the effects of recombinant adeno-associated virus (rAAV)-mediated CYP2J2 overexpression on angiotensin (Ang) II-induced AAA in apoE-defi cient mice. rAAV-CYP2J2 delivery led to an abundant aortic CYP2J2 expression and increased EETs generation. It was shown that CYP2J2 overexpression attenuated matrix metalloproteinase expression and activity, elastin degradation, and AAA formation, which was associated with reduced aortic infl ammation and macrophage infi ltration. In cultured vascular smooth muscle cells (VSMCs), rAAVmediated CYP2J2 overexpression and EETs markedly suppressed Ang II-induced infl ammatory cytokine expression. Moreover, overexpressed CYP2J2 and EETs inhibited Ang II-induced macrophage migration in a VSMC-macrophage coculture system. We further indicated that these protective effects were mediated by peroxisome proliferatoractivated receptor (PPAR) ␥ activation. Taken together, these results provide evidence that rAAV-mediated CYP2J2 overexpression prevents AAA development which is likely via PPAR ␥ activation and anti-infl ammatory action, suggesting that increasing EETs levels could be considered as a potential strategy to prevent and treat AAA. 25 February 2013. Published, JLR Papers in Press, February 26, 2013 DOI 10.1194 , apoE-defi ci...

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“…Consistently, therapies against atherosclerosis have not been effective in treating AAA in humans [10,80]. Animal studies have been in agreement with these findings as a clear dissociation between atherosclerotic lesions and aortic aneurysm formation has been reported [58,73,81]. MMP3 -/-/ApoE -/-mice (on cholesterol-rich diet) showed reduced frequency of aortic aneurysm formation despite sustained prevalence of atherosclerotic lesions compared to ApoeE -/-mice [58].…”

Section: Aortic Aneurysm Occurs Independently From Hypertension and Asupporting

confidence: 74%

Extracellular Matrix Remodelling and Abdominal Aortic Aneurysm

Basu¹,

Kassiri

2013

J Clin Exp Cardiolog

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Aorta is the largest artery in the body. Aortic wall is comprised of an intricate arrangement of extracellular matrix (ECM) structural proteins, primarily collagen and elastin, and layers of vascular smooth muscle cells. This gives the aortic wall the tensile strength to withstand the pressure of blood pumped from the heart during systole, and the elasticity to expand and accommodate the left ventricular stroke volume and to, subsequently, recoil to its original diameter and push the blood forward for systemic perfusion. Aortic aneurysm involves structural degradation of the aortic wall and focal dilatation of the aortic lumen. It is a devastating health problem with no effective treatment. Current management strategies for AAA patients include antihypertensive drugs and surgical repair for severe cases of AAA which are not without limitations and complications. A number of proteases (matrix metalloproteinases, serine and cystein proteases), and their inhibitors (tissue inhibitor of metalloproteases and cystatin) have been shown to contribute to AAA development and progression. In this review we will summarize the published literature on the role of ECM-regulatory proteins, mainly proteases and their inhibitors, in aortic function and aneurysm formation, with a focus on abdominal aortic aneurysm.

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Statins exert differential effects on angiotensin II-induced atherosclerosis, but no benefit for abdominal aortic aneurysms

Cited by 25 publications

References 28 publications

Deficiency of Endogenous Acute-Phase Serum Amyloid A Protects apoE ^−/− Mice From Angiotensin II–Induced Abdominal Aortic Aneurysm Formation

Deficiency of Endogenous Acute-Phase Serum Amyloid A Protects apoE ^−/− Mice From Angiotensin II–Induced Abdominal Aortic Aneurysm Formation

CYP2J2 overexpression increases EETs and protects against angiotensin II-induced abdominal aortic aneurysm in mice

Extracellular Matrix Remodelling and Abdominal Aortic Aneurysm

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Statins exert differential effects on angiotensin II-induced atherosclerosis, but no benefit for abdominal aortic aneurysms

Cited by 25 publications

References 28 publications

Deficiency of Endogenous Acute-Phase Serum Amyloid A Protects apoE −/− Mice From Angiotensin II–Induced Abdominal Aortic Aneurysm Formation

Deficiency of Endogenous Acute-Phase Serum Amyloid A Protects apoE −/− Mice From Angiotensin II–Induced Abdominal Aortic Aneurysm Formation

CYP2J2 overexpression increases EETs and protects against angiotensin II-induced abdominal aortic aneurysm in mice

Extracellular Matrix Remodelling and Abdominal Aortic Aneurysm

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Deficiency of Endogenous Acute-Phase Serum Amyloid A Protects apoE ^−/− Mice From Angiotensin II–Induced Abdominal Aortic Aneurysm Formation

Deficiency of Endogenous Acute-Phase Serum Amyloid A Protects apoE ^−/− Mice From Angiotensin II–Induced Abdominal Aortic Aneurysm Formation