Aneurysm severity is suppressed by deletion of CCN4

AbstractPatients with abdominal aortic aneurysms are frequently treated with high-risk surgery. A pharmaceutical treatment to reverse aneurysm progression could prevent the need for surgery and save both lives and healthcare resources. Since CCN4 regulates cell migration, proliferation and apoptosis, processes involved in aneurysm progression, it is a potential regulator of aneurysm progression. We investigated the role of CCN4 in a mouse aneurysm model, using apolipoprotein-E knockout (ApoE−/−) mice fed high fat diet and infused with Angiotensin II (AngII). Blood pressure was similarly elevated in CCN4−/−ApoE−/− mice and CCN4+/+ApoE−/− mice (controls) in response to AngII infusion. Deletion of CCN4 significantly reduced the number of ruptured aortae, both thoracic and abdominal aortic area, and aneurysm grade score, compared to controls. Additionally, the frequency of vessel wall remodelling and the number of elastic lamina breaks was significantly suppressed in CCN4−/−ApoE−/− mice compared to controls. Immunohistochemistry revealed a significantly lower proportion of macrophages, while the proportion of smooth muscle cells was not affected by the deletion of CCN4. There was also a reduction in both proliferation and apoptosis in CCN4−/−ApoE−/− mice compared to controls. In vitro studies showed that CCN4 significantly increased monocyte adhesion beyond that seen with TNFα and stimulated macrophage migration by more than threefold. In summary, absence of CCN4 reduced aneurysm severity and improved aortic integrity, which may be the result of reduced macrophage infiltration and cell apoptosis. Inhibition of CCN4 could offer a potential therapeutic approach for the treatment of aneurysms.

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Cyclic nucleotide phosphodiesterase 1C contributes to abdominal aortic aneurysm

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2107898118 ◽

2021 ◽

Vol 118 (31) ◽

pp. e2107898118

Author(s):

Chongyang Zhang ◽

Hongmei Zhao ◽

Yujun Cai ◽

Jian Xiong ◽

Amy Mohan ◽

...

Keyword(s):

Abdominal Aortic Aneurysm ◽

Aortic Aneurysm ◽

Cyclic Nucleotide ◽

Aortic Aneurysms ◽

Cyclic Nucleotide Phosphodiesterase ◽

Causative Role ◽

Abdominal Aortic

Abdominal aortic aneurysm (AAA) is characterized by aorta dilation due to wall degeneration, which mostly occurs in elderly males. Vascular aging is implicated in degenerative vascular pathologies, including AAA. Cyclic nucleotide phosphodiesterases, by hydrolyzing cyclic nucleotides, play critical roles in regulating vascular structure remodeling and function. Cyclic nucleotide phosphodiesterase 1C (PDE1C) expression is induced in dedifferentiated and aging vascular smooth muscle cells (SMCs), while little is known about the role of PDE1C in aneurysm. We observed that PDE1C was not expressed in normal aorta but highly induced in SMC-like cells in human and murine AAA. In mouse AAA models induced by Angiotensin II or periaortic elastase, PDE1C deficiency significantly decreased AAA incidence, aortic dilation, and elastin degradation, which supported a causative role of PDE1C in AAA development in vivo. Pharmacological inhibition of PDE1C also significantly suppressed preestablished AAA. We showed that PDE1C depletion antagonized SMC senescence in vitro and/or in vivo, as assessed by multiple senescence biomarkers, including senescence-associated β-galactosidase activity, γ-H2AX foci number, and p21 protein level. Interestingly, the role of PDE1C in SMC senescence in vitro and in vivo was dependent on Sirtuin 1 (SIRT1). Mechanistic studies further showed that cAMP derived from PDE1C inhibition stimulated SIRT1 activation, likely through a direct interaction between cAMP and SIRT1, which leads to subsequent up-regulation of SIRT1 expression. Our findings provide evidence that PDE1C elevation links SMC senescence to AAA development in both experimental animal models and human AAA, suggesting therapeutical significance of PDE1C as a potential target against aortic aneurysms.

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Effects of long-term chloroquine administration on the natural history of aortic aneurysms in mice

Canadian Journal of Physiology and Pharmacology ◽

10.1139/cjpp-2015-0068 ◽

2015 ◽

Vol 93 (8) ◽

pp. 641-648 ◽

Cited By ~ 8

Author(s):

Azza Ramadan ◽

Mark D. Wheatcroft ◽

Adrian Quan ◽

Krishna K. Singh ◽

Fina Lovren ◽

...

Keyword(s):

Natural History ◽

Thrombus Formation ◽

Aortic Aneurysms ◽

Ang Ii ◽

Abdominal Aortic ◽

Suprarenal Aorta ◽

History Of ◽

Categorical Distribution

Autophagy regulates cellular homeostasis and integrates the cellular pro-survival machinery. We investigated the role of autophagy in the natural history of murine abdominal aortic aneurysms (AAA). ApoE−/− mice were implanted with saline- or angiotensin II (Ang-II)-filled miniosmotic pumps then treated with either the autophagy inhibitor chloroquine (CQ; 50 mg·(kg body mass)–1·day–1, by intraperitoneal injection) or saline. Ang-II-elicited aneurysmal expansion of the suprarenal aorta coupled with thrombus formation were apparent 8 weeks later. CQ had no impact on the incidence (50% for Ang-II compared with 46.2% for Ang-II + CQ; P = NS) and categorical distribution of aneurysms. The markedly reduced survival rate observed with Ang-II (57.1% for Ang-II compared with 100% for saline; P < 0.05) was unaffected by CQ (61.5% for Ang-II + CQ; P = NS compared with Ang-II). CQ did not affect the mean maximum suprarenal aortic diameter (1.91 ± 0.19 mm for Ang-II compared with 1.97 ± 0.21 mm for Ang-II + CQ; P = NS). Elastin fragmentation, collagen accumulation, and smooth muscle attrition, which were higher in Ang-II-treated mice, were unaffected by CQ treatment. Long-term CQ administration does not affect the natural history and prognosis of experimental AAA, suggesting that global loss of autophagy is unlikely to be a causal factor in the development of aortic aneurysms. Manipulation of autophagy as a mechanism to reduce AAA may need re-evaluation.

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Neuropeptide Y (NPY) promotes inflammation-induced tumorigenesis by enhancing epithelial cell proliferation

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00410.2015 ◽

2017 ◽

Vol 312 (2) ◽

pp. G103-G111 ◽

Cited By ~ 12

Author(s):

Sabrina Jeppsson ◽

Shanthi Srinivasan ◽

Bindu Chandrasekharan

Keyword(s):

Cell Proliferation ◽

Epithelial Cell ◽

Neuropeptide Y ◽

Intestinal Inflammation ◽

Enteric Neurons ◽

Intestinal Epithelial ◽

Epithelial Proliferation ◽

Proliferation And Apoptosis

We have demonstrated that neuropeptide Y (NPY), abundantly produced by enteric neurons, is an important regulator of intestinal inflammation. However, the role of NPY in the progression of chronic inflammation to tumorigenesis is unknown. We investigated whether NPY could modulate epithelial cell proliferation and apoptosis, and thus regulate tumorigenesis. Repeated cycles of dextran sodium sulfate (DSS) were used to model inflammation-induced tumorigenesis in wild-type (WT) and NPY knockout ( NPY−/−) mice. Intestinal epithelial cell lines (T84) were used to assess the effects of NPY (0.1 µM) on epithelial proliferation and apoptosis in vitro. DSS-WT mice exhibited enhanced intestinal inflammation, polyp size, and polyp number (7.5 ± 0.8) compared with DSS- NPY−/− mice (4 ± 0.5, P < 0.01). Accordingly, DSS-WT mice also showed increased colonic epithelial proliferation (PCNA, Ki67) and reduced apoptosis (TUNEL) compared with DSS- NPY−/− mice. The apoptosis regulating microRNA, miR-375, was significantly downregulated in the colon of DSS-WT (2-fold, P < 0.01) compared with DSS- NPY−/−-mice. In vitro studies indicated that NPY promotes cell proliferation (increase in PCNA and β-catenin, P < 0.05) via phosphatidyl-inositol-3-kinase (PI3-K)-β-catenin signaling, suppressed miR-375 expression, and reduced apoptosis (increase in phospho-Bad). NPY-treated cells also displayed increased c-Myc and cyclin D1, and reduction in p21 ( P < 0.05). Addition of miR-375 inhibitor to cells already treated with NPY did not further enhance the effects induced by NPY alone. Our findings demonstrate a novel regulation of inflammation-induced tumorigenesis by NPY-epithelial cross talk as mediated by activation of PI3-K signaling and downregulation of miR-375. NEW & NOTEWORTHY Our work exemplifies a novel role of neuropeptide Y (NPY) in regulating inflammation-induced tumorigenesis via two modalities: first by enhanced proliferation (PI3-K/pAkt), and second by downregulation of microRNA-375 (miR-375)-dependent apoptosis in intestinal epithelial cells. Our data establish the existence of a microRNA-mediated cross talk between enteric neurons producing NPY and intestinal epithelial cells, and the potential of neuropeptide-regulated miRNAs as potential therapeutic molecules for the management of inflammation-associated tumors in the gut.

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Ruptured Abdominal Aortic Aneurysms: Role of Endovascular Therapy

Mount Sinai Journal of Medicine A Journal of Translational and Personalized Medicine ◽

10.1002/msj.20182 ◽

2010 ◽

Vol 77 (3) ◽

pp. 250-255 ◽

Cited By ~ 5

Author(s):

Neal S. Cayne ◽

Frank J. Veith

Keyword(s):

Endovascular Therapy ◽

Abdominal Aortic Aneurysms ◽

Aortic Aneurysms ◽

Abdominal Aortic ◽

Ruptured Abdominal Aortic Aneurysms

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Abstract 116: Simvastatin Affects Monocyte Adhesion and Infiltrative Activity in Patients With Abdominal Aortic Aneurysms

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.34.suppl_1.116 ◽

2014 ◽

Vol 34 (suppl_1) ◽

Author(s):

Kiana M Samadzadeh ◽

Anthony Nguyen ◽

Kevin C Chun ◽

Eugene S Lee

Keyword(s):

Abdominal Aortic Aneurysms ◽

Statin Treatment ◽

Aortic Aneurysms ◽

Monocyte Adhesion ◽

Abdominal Aortic ◽

Monocyte Cell ◽

High Concentrations ◽

Statin Drugs ◽

Monocyte Adherence

Purpose: The pleiotropic effects of statin drugs on reducing inflammation have been well regarded in decreasing AAA expansion. We hypothesize that increased monocyte activity plays a central role in AAA formation and expansion. This study examines whether statins can prevent monocyte cell adhesion, transmigration, and matrix metalloproteinase (MMP) and inhibitor (TIMP) concentrations in AAA patients compared to non-AAA patients. Methods: Peripheral blood was collected for monocyte and serum isolation from control (n=4) and AAA (n=8) patients. Monocyte adhesion and transmigration were assessed under untreated, statin treated, and statin + mevalonate (statin inhibitor) treated conditions in vitro. Luminex assays determined MMP and TIMP concentrations from cell culture and patient serum. Results: Untreated AAA patient monocytes showed higher levels of adhesion (p=0.05) and transmigration (p=0.04) compared to control subjects (Figure 1A & 1B). Statin treatment caused a decrease in AAA monocyte adherence to the endothelium (p=0.03) and high concentrations of mevalonate reversed statin treatment effects (p=0.04) (Figure 1A). A similar trend was noted in monocyte transmigration (Figure 1B). Higher concentrations of MMP-9 were found in AAA patient serum compared to controls (p=0.01) (Figure 1C). TIMP-4 concentration were decreased in AAA patients compared to controls (p=0.02) (Figure 1D). Conclusions: Statins reduce monocyte interaction with the endothelium in vitro, leading to decreased levels of MMP-9 and increased levels of TIMP-4, implying a possible mechanism by which statins reduce AAA expansion.

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Regression of a Descending Thoracoabdominal Aortic Dissection following Staged Deployment of Thoracic and Abdominal Aortic Endografts

Journal of Endovascular Therapy ◽

10.1177/15266028020090s215 ◽

2002 ◽

Vol 9 (2_suppl) ◽

pp. II-92-II-97 ◽

Cited By ~ 2

Author(s):

Rodney A. White ◽

Carlos Donayre ◽

Irwin Walot ◽

James Lee ◽

George E. Kopchok

Keyword(s):

Aortic Dissection ◽

Stent Graft ◽

False Lumen ◽

Acute Chest Pain ◽

Aortic Aneurysms ◽

Abdominal Aneurysm ◽

Entry Site ◽

Abdominal Aortic ◽

Thoracic And Abdominal ◽

Thoracic Stent Graft

Purpose: To describe the successful endovascular repair and regression of an extensive descending thoracoabdominal aortic dissection associated with thoracic and abdominal aortic aneurysms. Case Report: An 83-year-old man presented with acute chest pain and shortness of breath. A descending thoracoabdominal aortic dissection that extended from near the left subclavian artery (LSA) to the right common iliac artery was found on computed tomography. Separate aneurysms in the thoracic and abdominal aorta were also identified. Staged endovascular procedures were undertaken to (1) close the single entry site and exclude the aneurysm in the thoracic aorta with an AneuRx thoracic stent-graft, (2) exclude the abdominal aneurysm and distal re-entry site with a bifurcated AneuRx endograft, and (3) treat a newly dilated thoracic segment between the LSA and first thoracic stent-graft. At 1 year, the false lumen had completely disappeared, the thoracic aneurysm had collapsed onto the endograft, and the abdominal aneurysm had shrunk by 30%. Conclusions: The potential to treat extensive aortic dissections with the hope that they might regress is promising, but repair of highly complex lesions involving one or more aneurysms in addition to the dissection requires meticulous imaging studies both preoperatively and intraprocedurally.

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