Pathogenesis of Thoracic and Abdominal Aortic Aneurysms

Guo, Dong; Papke, Christina L.; He, Rong; Milewicz, Dianna M.

doi:10.1196/annals.1383.013

Cited by 231 publications

(193 citation statements)

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“…1 Aortic aneurysm manifests as either thoracic or abdominal aortic aneurysm (AAA). 2 AAA has a high prevalence in aged men, whereas thoracic aortic aneurysm exhibits no sex propensity but has a greater prevalence in younger individuals. 2 Irrespective of the type, it is well known that activation of the renineangiotensin (Ang) system, with a consequent increase in the production of Ang II, promotes the development of aneurysms.…”

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confidence: 99%

“…2 AAA has a high prevalence in aged men, whereas thoracic aortic aneurysm exhibits no sex propensity but has a greater prevalence in younger individuals. 2 Irrespective of the type, it is well known that activation of the renineangiotensin (Ang) system, with a consequent increase in the production of Ang II, promotes the development of aneurysms. 1 It has been established that the expression of the Apoe gene is altered in patients with AAA, 3 and that Apoe À/À mice receiving exogenous Ang II develop AAA, and are therefore used as a model for human AAA.…”

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confidence: 99%

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Cytochrome P450 1B1 Contributes to the Development of Angiotensin II–Induced Aortic Aneurysm in Male Apoe−/− Mice

Thirunavukkarasu

Khan

Song

et al. 2016

The American Journal of Pathology

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Cytochrome P450 (CYP) 1B1 is implicated in vascular smooth muscle cell migration, proliferation, and hypertension. We assessed the contribution of CYP1B1 to angiotensin (Ang) IIeinduced abdominal aortic aneurysm (AAA). Male Apoe À/À /Cyp1b1 þ/þ and Apoe À/À /Cyp1b1 À/À mice were infused with Ang II or its vehicle for 4 weeks; another group of Apoe À/À /Cyp1b1 þ/þ mice was coadministered the CYP1B1 inhibitor 2,3 0 ,4,5 0 -tetramethoxystilbene (TMS) every third day for 4 weeks. On day 28 of Ang II infusion, AAAs were analyzed by ultrasound and ex vivo by Vernier calipers, mice were euthanized, and tissues were harvested. Ang II produced AAAs in Apoe À/À /Cyp1b1 þ/þ mice; mice treated with TMS or Apoe À/À /Cyp1b1 À/À mice had reduced AAAs. Ang II enhanced infiltration of macrophages, T cells, and platelets and increased plateletderived growth factor D, Pdgfrb, Itga2, and matrix metalloproteinases 2 and 9 expression in aortic lesions; these changes were inhibited in mice treated with TMS and in Apoe À/À /Cyp1b1 À/À mice. Oxidative stress resulted in cyclooxygenase-2 expression in aortic lesions. These effects were minimized in Apoe À/À / Cyp1b1 þ/þ mice treated with TMS and in Apoe À/À /Cyp1b1 À/À mice and by concurrent treatment with the superoxide scavenger 4-hydroxyl-2,2,6,6-tetramethylpiperidine-1-oxyl. CYP1B1 contributed to the development of Ang IIeinduced AAA and associated pathogenic events in mice, likely by enhancing oxidative stress and associated signaling events. Thus, CYP1B1 may serve as a target for therapeutic agents for AAA in males. (Am J Pathol 2016 http://dx

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confidence: 99%

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confidence: 99%

Cytochrome P450 1B1 Contributes to the Development of Angiotensin II–Induced Aortic Aneurysm in Male Apoe−/− Mice

Thirunavukkarasu

Khan

Song

et al. 2016

The American Journal of Pathology

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“…1,2 Aortic medial degeneration, histopathologically characterized by loss of elastin fibers and smooth muscle cells and increased proteoglycan deposition, is thought to precede TAAD. 3 TAAD can be classified as sporadic, syndromic and familial non-syndromic. 4 Sporadic forms of TAAD tend to develop at an older age and their main risk factor is hypertension.…”

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confidence: 99%

Incomplete segregation of MYH11 variants with thoracic aortic aneurysms and dissections and patent ductus arteriosus

et al. 2012

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Thoracic aortic aneurysms and dissections (TAAD) is a serious condition with high morbidity and mortality. It is estimated that 20% of non-syndromic TAAD cases are inherited in an autosomal-dominant pattern with variable expression and reduced penetrance. Mutations in myosin heavy chain 11 (MYH11), one of several identified TAAD genes, were shown to simultaneously cause TAAD and patent ductus arteriosus (PDA). We identified two large Dutch families with TAAD/PDA and detected two different novel heterozygote MYH11 variants in the probands. These variants, a heterozygote missense variant and a heterozygote in-frame deletion, were predicted to have damaging effects on protein structure and function. However, these novel alterations did not segregate with the TAAD/PDA in 3 out of 11 cases in family TAAD01 and in 2 out of 6 cases of family TAAD02. No mutation was detected in other known TAAD genes. Thus, it is expected that within these families other genetic factors contribute to the disease either by themselves or by interacting with the MYH11 variants. Such an oligogenic model for TAAD would explain the variable onset and progression of the disorder and its reduced penetrance in general. We conclude that in familial TAAD/PDA with an MYH11 variant in the index case caution should be exercised upon counseling family members. Specialized surveillance should still be offered to the non-carriers to prevent catastrophic aortic dissections or ruptures. Furthermore, our study underscores that segregation analysis remains very important in clinical genetics. Prediction programs and mutation evaluation algorithms need to be interpreted with caution.

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“…Thoracic aortic aneurysms tend to be asymptomatic and usually are not noticed before thoracic aortic dissection (TAD) occurs. It is believed that TAD is a complex trait that is caused by both environmental and genetic factors [2][3][4] . Genetic susceptibility is an important risk factor for TAD.…”

Section: Introductionmentioning

confidence: 99%

Genetic analysis of six SNPs in candidate genes associated with high cross-race risk of development of thoracic aortic aneurysms and dissections in Chinese Han population

et al. 2010

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Aim: Genetic susceptibility is an important risk factor for aortic aneurysm and dissection. Recent case-control association studies have identified six single nucleotide polymorphisms (SNPs) associated with abdominal aortic aneurysm (AAA) in a Caucasian population. We aimed to determine whether these loci confer susceptibility to thoracic aortic dissection (TAD) in a Chinese Han population and thus to establish cross-race susceptibility to TAD. Methods: This study analyzed blood DNA isolated from 206 TAD patients and 180 controls from the ethnic Chinese Han population. Six SNPs -rs819146, rs8003379, rs2853523, rs326118, rs3788205, and rs10757278 -were genotyped using high-throughput matrix-assisted laser desorption ionization-time-of-flight (MALDI-TOF) mass spectrometry. Results: The A allele frequency for the SNP on 9p21, tagged as rs10757278, was higher in male TAD patients than in male controls (P=0.017). Moreover, with adjustment for traditional cardiovascular risk factors (sex, age, hypertension, dyslipidemia, diabetes, and smoking), the rs10757278 [odds ratio (OR) 0.63, 95% confidence interval (CI) 0.43 to 0.93] polymorphism was found to be an independent susceptibility factor for TAD in men. Conclusion: Our results suggest that a sequence variant on 9p21 is an important susceptibility locus that confers high cross-race risk for development of TAD in Chinese Han population.

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Pathogenesis of Thoracic and Abdominal Aortic Aneurysms

Cited by 231 publications

References 59 publications

Cytochrome P450 1B1 Contributes to the Development of Angiotensin II–Induced Aortic Aneurysm in Male Apoe−/− Mice

Cytochrome P450 1B1 Contributes to the Development of Angiotensin II–Induced Aortic Aneurysm in Male Apoe−/− Mice

Incomplete segregation of MYH11 variants with thoracic aortic aneurysms and dissections and patent ductus arteriosus

Genetic analysis of six SNPs in candidate genes associated with high cross-race risk of development of thoracic aortic aneurysms and dissections in Chinese Han population

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