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6. Abstract 18753: Dynamic Phenotypic Transition of Smooth Muscle Cells During Human Ascending Thoracic Aortic Disease Progression: From Compensation in Aortic Aneurysm to Decompensation in Aortic Dissection

Author

Li, Yanming, Zhang, Chen, Vasquez, Hernan, Li, Yang, Chakraborty, Abhijit, Rebello, Kimberly, Xu, Samantha, Zhang, Lin, Sawada, Hisashi, Zhou, Zhen, Chen, Rui, li, yumei, Saeys, Yvan, eisenberg, steven, Lu, Hong S, Cassis, Lisa A, Coselli, Joseph S, Daugherty, Alan, Milewicz, Dianna M, Shen, Ying H, and Lemaire, Scott A

Published
2023
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10. Renal Proximal Tubule Cell-specific Megalin Deletion Induces Tubulointerstitial Nephritis in Mice Fed Western Diet

Author

Amioka, Naofumi, primary, Franklin, Michael K, additional, Kukida, Masayoshi, additional, Sawada, Hisashi, additional, Moorleghen, Jessica J, additional, Howatt, Deborah A, additional, Katsumata, Yuriko, additional, Mullick, Adam E, additional, Yanagita, Motoko, additional, Martinez-Irizarry, Michelle, additional, Sandoval, Ruben M, additional, Dunn, Kenneth W, additional, Daugherty, Alan, additional, and Lu, Hong S., additional

Published
2024
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11. Adropin: An endocrine link between the biological clock and cholesterol homeostasis

Author

Ghoshal, Sarbani, Stevens, Joseph R, Billon, Cyrielle, Girardet, Clemence, Sitaula, Sadichha, Leon, Arthur S, Rao, DC, Skinner, James S, Rankinen, Tuomo, Bouchard, Claude, Nuñez, Marinelle V, Stanhope, Kimber L, Howatt, Deborah A, Daugherty, Alan, Zhang, Jinsong, Schuelke, Matthew, Weiss, Edward P, Coffey, Alisha R, Bennett, Brian J, Sethupathy, Praveen, Burris, Thomas P, Havel, Peter J, and Butler, Andrew A

Subjects
Biochemistry and Cell Biology, Biological Sciences, Genetics, Atherosclerosis, Nutrition, Digestive Diseases, Liver Disease, Obesity, Prevention, 1.1 Normal biological development and functioning, Metabolic and endocrine, Adult, Aged, Animals, Blood Proteins, Cells, Cultured, Cholesterol, LDL, Circadian Clocks, Female, Glucose, Hep G2 Cells, Homeostasis, Humans, Intercellular Signaling Peptides and Proteins, Liver, Macaca mulatta, Male, Mice, Middle Aged, Nuclear Receptor Subfamily 1, Group F, Member 1, Nuclear Receptor Subfamily 1, Group F, Member 3, Peptides, Proteins, Cholesterol, LDL, Cardiovascular disease, Adropin, Sex, Physiology, Biochemistry and cell biology
Abstract

ObjectiveIdentify determinants of plasma adropin concentrations, a secreted peptide translated from the Energy Homeostasis Associated (ENHO) gene linked to metabolic control and vascular function.MethodsAssociations between plasma adropin concentrations, demographics (sex, age, BMI) and circulating biomarkers of lipid and glucose metabolism were assessed in plasma obtained after an overnight fast in humans. The regulation of adropin expression was then assessed in silico, in cultured human cells, and in animal models.ResultsIn humans, plasma adropin concentrations are inversely related to atherogenic LDL-cholesterol (LDL-C) levels in men (n = 349), but not in women (n = 401). Analysis of hepatic Enho expression in male mice suggests control by the biological clock. Expression is rhythmic, peaking during maximal food consumption in the dark correlating with transcriptional activation by RORα/γ. The nadir in the light phase coincides with the rest phase and repression by Rev-erb. Plasma adropin concentrations in nonhuman primates (rhesus monkeys) also exhibit peaks coinciding with feeding times (07:00 h, 15:00 h). The ROR inverse agonists SR1001 and the 7-oxygenated sterols 7-β-hydroxysterol and 7-ketocholesterol, or the Rev-erb agonist SR9009, suppress ENHO expression in cultured human HepG2 cells. Consumption of high-cholesterol diets suppress expression of the adropin transcript in mouse liver. However, adropin over expression does not prevent hypercholesterolemia resulting from a high cholesterol diet and/or LDL receptor mutations.ConclusionsIn humans, associations between plasma adropin concentrations and LDL-C suggest a link with hepatic lipid metabolism. Mouse studies suggest that the relationship between adropin and cholesterol metabolism is unidirectional, and predominantly involves suppression of adropin expression by cholesterol and 7-oxygenated sterols. Sensing of fatty acids, cholesterol and oxysterols by the RORα/γ ligand-binding domain suggests a plausible functional link between adropin expression and cellular lipid metabolism. Furthermore, the nuclear receptors RORα/γ and Rev-erb may couple adropin synthesis with circadian rhythms in carbohydrate and lipid metabolism.

Published
2018

15. Neutrophil Elastase Inhibition by Sivelestat (ONO-5046) Attenuates AngII-Induced Abdominal Aortic Aneurysms in Apolipoprotein E-Deficient Mice.

Author

Hada, Yoshiko, Uchida, Haruhito A, Okamoto, Shugo, Otaka, Nozomu, Katayama, Katsuyoshi, Subramanian, Venkateswaran, Daugherty, Alan, and Wada, Jun

Subjects
LEUCOCYTE elastase, ABDOMINAL aortic aneurysms, ARTERIAL diseases, ANGIOTENSIN II, MUSCLE cells, ELASTASES
Abstract

BACKGROUND Abdominal aortic aneurysm (AAA) is an arterial disease characterized by dilatation of the aortic wall. It has been suggested that neutrophil counts and neutrophil elastase activity are associated with AAA. We investigated whether a neutrophil elastase (NE) inhibitor, sivelestat (Siv), had a protective effect against angiotensin II (AngII)-induced AAAs. METHODS Male apolipoprotein E-deficient mice were assigned into three groups: Vehicle + saline, AngII + saline, and AngII + Siv. All mice were administered intraperitoneally with either Siv or vehicle twice daily after AngII infusion. RESULTS In the 4-week AngII infusion study, plasma NE concentration (P  = 0.041) and its activity (P  = 0.011) were elevated by AngII. These increases were attenuated by Siv (concentration: P  = 0.010, activity: P  = 0.027). Further, plasma elastase activity was closely correlated with aortic width (R  = 0.6976, P  < 0.001). In the 1-week AngII infusion study, plasma and tissue elastase activity increased by AngII (plasma: P  = 0.034, tissue: P  < 0.001), but were reduced by Siv (plasma: P  = 0.014, tissue: P  = 0.024). AngII increased aortic width (P  = 0.011) but was attenuated by co-administration of Siv (P  = 0.022). Moreover, Siv decreased the incidence of AAAs (P  = 0.009). Elastin fragmentation induced by AngII was reduced by Siv. Many inflammatory cells that were either CD68 or Gr-1 positive were observed in the AngII + saline group, whereas few inflammatory cells were accumulated in the AngII + Siv group. MMP-2 and MMP-9 were enhanced by AngII, but were reduced by Siv. In vitro , MMP-2 activity was induced by human NE (medium: P  < 0.001, cells: P  = 0.001), which was attenuated by co-incubation of Siv in medium (P  < 0.001) and protein of human aortic smooth muscle cells (P  = 0.001). CONCLUSIONS Siv attenuated AngII-induced AAA through the inhibition of NE. [ABSTRACT FROM AUTHOR]

Published
2024
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19. Exome-wide evaluation of rare coding variants using electronic health records identifies new gene–phenotype associations

Author

Park, Joseph, Lucas, Anastasia M., Zhang, Xinyuan, Chaudhary, Kumardeep, Cho, Judy H., Nadkarni, Girish, Dobbyn, Amanda, Chittoor, Geetha, Josyula, Navya S., Katz, Nathan, Breeyear, Joseph H., Ahmadmehrabi, Shadi, Drivas, Theodore G., Chavali, Venkata R. M., Fasolino, Maria, Sawada, Hisashi, Daugherty, Alan, Li, Yanming, Zhang, Chen, Bradford, Yuki, Weaver, JoEllen, Verma, Anurag, Judy, Renae L., Kember, Rachel L., Overton, John D., Reid, Jeffrey G., Ferreira, Manuel A. R., Li, Alexander H., Baras, Aris, LeMaire, Scott A., Shen, Ying H., Naji, Ali, Kaestner, Klaus H., Vahedi, Golnaz, Edwards, Todd L., Chen, Jinbo, Damrauer, Scott M., Justice, Anne E., Do, Ron, Ritchie, Marylyn D., and Rader, Daniel J.

Published
2021
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24. Manipulation of components of the renin angiotensin system in renal proximal tubules fails to alter atherosclerosis in hypercholesterolemic mice

Author

Kukida, Masayoshi, primary, Amioka, Naofumi, additional, Ye, Dien, additional, Chen, Hui, additional, Moorleghen, Jessica J., additional, Liang, Ching-Ling, additional, Howatt, Deborah A., additional, Katsumata, Yuriko, additional, Yanagita, Motoko, additional, Sawada, Hisashi, additional, Daugherty, Alan, additional, and Lu, Hong S., additional

Published
2023
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29. American Heart Association Vascular Disease Strategically Focused Research Network

Author

Barnett, Joey V., Beckman, Joshua A., Bonaca, Marc P., Carnethon, Mercedes R., Cassis, Lisa A., Creager, Mark A., Daugherty, Alan, Feinberg, Mark W., Freiberg, Matthew S., Goodney, Philip P., Greenland, Philip, Leeuwenburgh, Christiaan, LeMaire, Scott A., McDermott, Mary M., Sabatine, Marc S., Shen, Ying H., Wasserman, David H., Webb, Nancy R., and Wells, Quinn S.

Published
2020
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30. Honoring the Life and Legacy of Dr David A. Dichek.

Author

Aikawa, Elena, Allison, Matthew A., Iruela Arispe, Luisa, Bendeck, Michelle P., Yabing Chen, Gardiner, Elizabeth E., Golledge, Jonathan, Suzuki-Inoue, Katsue, Marelli-Berg, Federica, Powell, Janet T., Ramasamy, Ravichandran, Sarpong, Daniel F., Sorci-Thomas, Mary G., Daugherty, Alan, Hegele, Robert A., and Schmidt, Ann Marie

Published
2024
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33. Angiotensin II infusion promotes ascending aortic aneurysms: attenuation by CCR2 deficiency in apoE−/− mice

Author

Daugherty, Alan, Rateri, Debra L, Charo, Israel F, Owens, A Phillip, Howatt, Deborah A, and Cassis, Lisa A

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Cardiovascular, Atherosclerosis, Hypertension, Rare Diseases, Aetiology, 2.1 Biological and endogenous factors, Angiotensin II, Animals, Aorta, Aortic Aneurysm, Apolipoproteins E, Blood Pressure, Body Weight, Cholesterol, Disease Models, Animal, Hypercholesterolemia, Lipids, Male, Mice, Mice, Knockout, Receptors, CCR2, Vasodilation, Medical and Health Sciences, Cardiovascular System & Hematology, Biomedical and clinical sciences, Health sciences
Abstract

AngII (angiotensin II) induces atherosclerosis and AAAs (abdominal aortic aneurysms) through multiple proposed mechanisms, including chemotaxis. Therefore, we determined the effects of whole-body deficiency of the chemokine receptor CCR2 (CC chemokine receptor 2) on these diseases. To meet this objective, apoE (apolipoprotein E)-/- mice that were either CCR2+/+ or CCR2-/-, were infused with either saline or AngII (1000 ng.kg-1 of body weight.min-1) for 28 days via mini-osmotic pumps. Deficiency of CCR2 markedly attenuated both atherosclerosis and AAAs, unrelated to systolic blood pressure or plasma cholesterol concentrations. During the course of the present study, we also observed that AngII infusion led to large dilatations that were restricted to the ascending aortic region of apoE-/- mice. The aortic media in most of the dilated area was thickened. In regions of medial thickening, distinct elastin layers were discernable. There was an expansion of the distance between elastin layers in a gradient from the intimal to the adventitial aspect of the media. This pathology differed in a circumscribed area of the anterior region of ascending aortas in which elastin breaks were focal and almost transmural. All regions of the ascending aorta of AngII-infused mice had diffuse medial macrophage accumulation. Deficiency of CCR2 greatly attenuated the AngII-induced lumen dilatation in the ascending aorta. This new model of ascending aortic aneurysms has pathology that differs markedly from AngII-induced atherosclerosis or AAAs, but all vascular pathologies were attenuated by CCR2 deficiency.

Published
2010

44. Abstract 15530: Single-cell Analysis in Aortic Aneurysmal Tissue From Patients With Marfan Syndrome Reveals Increased Tgf-beta Production but Downregulation of Downstream Canonical Tgf-beta Signaling Pathways

Author

Dawson, Ashley, Li, Yanming, Ren, Pingping, Vasquez, Hernan, Zhang, Chen, Appel, Richard, Ageedi, Waleed, Luo, Wei, Zhang, Lin, Li, Yang, Sheppard, Mary B, Lu, Hong S, Cassis, Lisa A, Coselli, Joseph S, Daugherty, Alan, Shen, Ying H, and Lemaire, Scott A

Published
2020
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48. Lipoproteins, inflammation, and vascular disease

Author

Daugherty, Alan

Subjects
616.13
Abstract

The major focus of the studies described in this thesis is the interaction of lipoproteins and inflammation in vascular diseases. Early studies describe the role of postprandial lipoproteins in the development of lipid-laden macro phages that are a hallmark of atherosclerotic lesions. These studies paved the way for subsequent studies on the role of lipoprotein modification in atherosclerosis. These included the discovery that LDL present in atherosclerotic lesions had properties that were consistent with oxidative modification. To determine whether this modification was a cause or consequence of the disease, studies were performed using antioxidants. These studies defined the effects of antioxidants on early and mature atherosclerotic lesions, as well as on iatrogenic vascular lesions. My laboratory also studied two potential enzymes that have the potential to generate oxidized lipoprotein; myeloperoxidase and 15-lipoxygenase. The effects of pharmacological inhibition and regulation on the latter enzyme were defined. Studies have also addressed the regulation and function of a major receptor for oxidized LDL, class A scavenger receptor. These include regulation, structure-function, and the effects of cell selective overexpression. These lipoprotein modifications have a well characterized role on the infiltration of macro phages and their subsequent engorgement with lipid. Aberrant lipoprotein metabolism may be a factor underlying the recruitment of T Iymphocytes into lesions. Generally, T Iymphocytes have an under appreciated role in the atherogenic process. Studies using mice deficient in Iymphocyte subclasses and specific cytokines are addressing the issue of this cell type in lesion formation. Finally, we have recently discovered a pronounced inflammatory role of angiotensin II that is associated with the development of atherosclerosis and abdominal aortic aneurysms

Published
2002

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