Dissections or ruptures of aortic aneurysms remain a leading cause of death in the developed world, with the majority of deaths being preventable if individuals at risk are identified and properly managed. Genetic variants predispose individuals to these aortic diseases. In the case of thoracic aortic aneurysm and dissections (thoracic aortic disease), genetic data can be used to identify some at-risk individuals and dictate management of the associated vascular disease. For abdominal aortic aneurysms, genetic associations have been identified, which provide insight on the molecular pathogenesis but cannot be used clinically yet to identify individuals at risk for abdominal aortic aneurysms. This compendium will discuss our current understanding of the genetic basis of thoracic aortic disease and abdominal aortic aneurysm disease. Although both diseases share several pathogenic similarities, including proteolytic elastic tissue degeneration and smooth muscle dysfunction, they also have several distinct differences, including population prevalence and modes of inheritance.

Genetics of Thoracic and Abdominal Aortic Diseases

RATIONALE: Abdominal aortic aneurysm (AAA) is a complex disease with both genetic and environmental risk factors. Together, 6 previously identified risk loci only explain a small proportion of the heritability of AAA. OBJECTIVE: To identify additional AAA risk loci using data from all available genome-wide association studies. METHODS AND RESULTS: Through a meta-analysis of 6 genome-wide association study data sets and a validation study totaling 10 204 cases and 107 766 controls, we identified 4 new AAA risk loci: 1q32.3 (SMYD2), 13q12.11 (LINC00540), 20q13.12 (near PCIF1/MMP9/ZNF335), and 21q22.2 (ERG). In various database searches, we observed no new associations between the lead AAA single nucleotide polymorphisms and coronary artery disease, blood pressure, lipids, or diabetes mellitus. Network analyses identified ERG, IL6R, and LDLR as modifiers of MMP9, with a direct interaction between ERG and MMP9. CONCLUSIONS: The 4 new risk loci for AAA seem to be specific for AAA compared with other cardiovascular diseases and related traits suggesting that traditional cardiovascular risk factor management may only have limited value in preventing the progression of aneurysmal disease.

/pdf/meta-analysis-of-genome-wide-association-studies-for-16cjzuiqu9.pdf

Meta-Analysis of Genome-Wide Association Studies for Abdominal Aortic Aneurysm Identifies Four New Disease-Specific Risk Loci

Abstract Cellular mechanotransduction, a critical regulator of numerous biological processes, is the conversion from mechanical signals to biochemical signals regarding cell activities and metabolism. Typical mechanical cues in organisms include hydrostatic pressure, fluid shear stress, tensile force, extracellular matrix stiffness or tissue elasticity, and extracellular fluid viscosity. Mechanotransduction has been expected to trigger multiple biological processes, such as embryonic development, tissue repair and regeneration. However, prolonged excessive mechanical stimulation can result in pathological processes, such as multi-organ fibrosis, tumorigenesis, and cancer immunotherapy resistance. Although the associations between mechanical cues and normal tissue homeostasis or diseases have been identified, the regulatory mechanisms among different mechanical cues are not yet comprehensively illustrated, and no effective therapies are currently available targeting mechanical cue-related signaling. This review systematically summarizes the characteristics and regulatory mechanisms of typical mechanical cues in normal conditions and diseases with the updated evidence. The key effectors responding to mechanical stimulations are listed, such as Piezo channels, integrins, Yes-associated protein (YAP) /transcriptional coactivator with PDZ-binding motif (TAZ), and transient receptor potential vanilloid 4 (TRPV4). We also reviewed the key signaling pathways, therapeutic targets and cutting-edge clinical applications of diseases related to mechanical cues. 

Cellular mechanotransduction in health and diseases: from molecular mechanism to therapeutic targets

The Nr4a family of nuclear hormone receptors is composed of three members—Nr4a1/Nur77, Nr4a2/Nurr1 and Nr4a3/Nor1. While currently defined as ligandless, these transcription factors have been shown to regulate varied processes across a host of tissues. Of particular interest, the Nr4a family impinge, in a tissue dependent fashion, on cellular proliferation, apoptosis and fuel utilization. The regulation of these processes occurs through both nuclear and non-genomic pathways. The purpose of this review is to provide a balanced perspective of the tissue specific and Nr4a family member specific, effects on cellular proliferation, apoptosis and fuel utilization.

https://www.mdpi.com/2073-4409/8/11/1373/pdf

Function of Nr4a Orphan Nuclear Receptors in Proliferation, Apoptosis and Fuel Utilization Across Tissues.

Abdominal aortic aneurysm (AAA) refers to the localized dilatation of the infra-renal aorta, in which the diameter exceeds 3.0 cm. Loss of vascular smooth muscle cells, degradation of the extracellular matrix (ECM), vascular inflammation, and oxidative stress are hallmarks of AAA pathogenesis and contribute to the progressive thinning of the media and adventitia of the aortic wall. With increasing AAA diameter, and left untreated, aortic rupture ensues with high mortality. Collective evidence of recent genetic and epigenetic studies has shown that phenotypic modulation of smooth muscle cells (SMCs) towards dedifferentiation and proliferative state, which associate with the ECM remodeling of the vascular wall and accompanied with increased cell senescence and inflammation, is seen in in vitro and in vivo models of the disease. This review critically analyses existing publications on the genetic and epigenetic mechanisms implicated in the complex role of SMCs within the aortic wall in AAA formation and reflects the importance of SMCs plasticity in AAA formation. Although evidence from the wide variety of mouse models is convincing, how this knowledge is applied to human biology needs to be addressed urgently leveraging modern in vitro and in vivo experimental technology.

Genetic and Epigenetic Mechanisms Underlying Vascular Smooth Muscle Cell Phenotypic Modulation in Abdominal Aortic Aneurysm

The orphan nuclear receptor 4A (NR4A) family plays critical roles in the regulation of cell proliferation, differentiation, and survival in the cardiovascular system. However, the molecular mechanisms underlying the regulation of NR4A receptor expression and its role in pulmonary artery smooth muscle cell (PASMC) function remain unclear. Here, we investigated whether the NR4A family regulates PASMC proliferation, and if so, which mechanisms are involved. By using quantitative real-time RT-PCR, we showed that the orphan nuclear receptor Nur77 was the most abundant member of NR4A family expressed in rat PASMCs, as compared with the two other members, NOR-1 and Nurr1. In rat PASMCs, expression of Nur77 was robustly induced in response to several pathologic stimuli of pulmonary arterial hypertension (PAH), such as hypoxia, 5-hydroxytryptamine (5-HT), platelet-derived growth factor, and endothelin-1. Importantly, Nur77 was also significantly increased in lungs of rats with monocrotaline-induced PAH. Furthermore, we demonstrated that 5-HT markedly up-regulated Nur77 expression through the mitogen-activated protein kinases/extracellular signal-regulated kinase 1/2 pathway. Overexpression of Nur77 inhibited 5-HT-induced PASMC proliferation, as well as the expression of cyclin D1 and proliferating cell nuclear antigen. Mechanistically, we demonstrated that Nur77 specifically interacts with signal transducer and activator of transcription 3, thus inhibiting its phosphorylation and expression of its target genes, such as Pim-1, nuclear factor of activated T cells c2, and survivin in PASMCs. These results indicate that Nur77 is a novel negative-feedback regulator of PASMC proliferation through inhibition of the signal transducer and activator of transcription 3/Pim-1/nuclear factor of activated T cells axis. Modulation of Nur77 activity may potentially represent a novel therapeutic strategy for the treatment of PAH.

/pdf/nur77-suppresses-pulmonary-artery-smooth-muscle-cell-4dofj7pfja.pdf

Nur77 Suppresses Pulmonary Artery Smooth Muscle Cell Proliferation through Inhibition of the STAT3/Pim-1/NFAT Pathway

Abdominal aortic aneurysm (AAA) is a common degenerative vascular disease whose pathogenesis is associated with activation of multiple signaling pathways including Jun NH2-terminal kinases (JNK) and NF-κB. It is now well recognized that these pathways are chaperoned by the heat shock protein 90 (Hsp90), suggesting that inhibition of Hsp90 may be a novel strategy for inhibiting AAAs. The aim of this study is to investigate whether inhibition of Hsp90 by 17-DMAG (17-dimethyl-aminothylamino-17-demethoxy-geldanamycin) attenuates ANG II-induced AAA formation in mice, and, if so, to elucidate the mechanisms involved. Apolipoprotein E-null mice were infused with ANG II to induce AAA formation and simultaneously treated by intraperitoneal injection with either vehicle or 17-DMAG for 4 wk. ANG II infusion induced AAA formation in 80% of mice, which was accompanied by increased matrix metalloproteinase (MMP) activity, enhanced tissue inflammation, oxidative stress, and neovascularization. Importantly, these effects were inhibited by 17-DMAG treatment. Mechanistically, we showed that 17-DMAG prevented the formation and progression of AAA through its inhibitory effects on diverse biological pathways including 1) by blocking ANG II-induced phosphorylation of ERK1/2 and JNK that are critically involved in the regulation of MMPs in vascular smooth muscle cells, 2) by inhibiting IκB kinase expression and expression of MCP-1, and 3) by attenuating ANG II-stimulated angiogenic processes critical to AAA formation. Our results demonstrate that inhibition of Hsp90 by 17-DMAG effectively attenuates ANG II-induced AAA formation by simultaneously inhibiting vascular inflammation, extracellular matrix degradation, and angiogenesis, which are critical in the formation and progression of AAAs.

https://www.physiology.org/doi/pdf/10.1152/ajpheart.00470.2014

Heat shock protein 90 inhibition by 17-DMAG attenuates abdominal aortic aneurysm formation in mice.

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Nur77 Suppresses Pulmonary Artery Smooth Muscle Cell Proliferation through Inhibition of the STAT3/Pim-1/NFAT Pathway

Heat shock protein 90 inhibition by 17-DMAG attenuates abdominal aortic aneurysm formation in mice.