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The Role of P2RX7 in Angiotensin II-Induced Hypertension and Cardiovascular Disease.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	The Role of P2RX7 in Angiotensin II-Induced Hypertension and Cardiovascular Disease./
作者:	Shokoples, Brandon.
面頁冊數:	1 online resource (263 pages)
附註:	Source: Dissertations Abstracts International, Volume: 84-10, Section: B.
Contained By:	Dissertations Abstracts International84-10B.
標題:	Lymphocytes. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=30346964click for full text (PQDT)
ISBN:	9798377672159

The Role of P2RX7 in Angiotensin II-Induced Hypertension and Cardiovascular Disease.
Shokoples, Brandon.

The Role of P2RX7 in Angiotensin II-Induced Hypertension and Cardiovascular Disease. - 1 online resource (263 pages)

Source: Dissertations Abstracts International, Volume: 84-10, Section: B.

Thesis (Ph.D.)--McGill University (Canada), 2022.

Includes bibliographical references

Hypertension affects more than one billion people worldwide and is the leading risk factor for burden of disease and mortality. It is associated with chronic low-grade inflammation and targets to diminish this low-grade inflammation are of interest. The purinergic receptor P2X7 (P2RX7) is activated by extracellular ATP and is a key regulator of inflammatory signalling, cellular death, and T lymphocyte development and function. Elevated plasma ATP levels have been observed in hypertensive patients, providing a potential mechanism for P2RX7 activation. Additionally, a hypomorphic polymorphism for P2X7 is correlated with a decreased risk for essential hypertension in Chinese post-menopausal women. The work in this thesis tests the hypothesis that P2RX7 mediates angiotensin (Ang) II-induced blood pressure elevation and cardiovascular injury by promoting the activation of innate and adaptive immune cells.In the first study, I assessed the contribution of P2RX7 to immune activation in hypertension and cardiovascular injury. Both P2rx7 knockout and P2RX7 antagonism attenuated Ang II (1000ng/kg/min) induced hypertension and small artery endothelial dysfunction. In addition, we found decreased infiltration of activated T cells into the aortic perivascular adipose tissue (PVAT) of Ang II-treated compared to wild-type (WT) control mice. Furthermore, WT mice treated with Ang II had an expansion of CD4+ and γδ T effector memory (TEM) cells in the spleen and aortic PVAT along with increased CD8+ TEM in the bone marrow. These changes were abrogated in P2rx7-/- mice or mice treated with a P2RX7 antagonist suggesting decreased immune activation in these mice. Neither P2rx7-/- mice nor P2RX7 antagonist-treated mice infused with Ang II were protected from cardiac dysfunction. In fact, Ang II-treated P2rx7-/- mice had reduced left ventricle fractional shortening and a dilated left ventricle compared to Ang II-treated WT mice, suggesting enhanced cardiac dysfunction. This study highlighted that P2rx7 knockout or P2RX7 antagonism attenuated Ang II-induced immune activation, and subsequent hypertension and vascular injury, but not cardiac dysfunction.In the second study, I aimed to delineate the role of P2RX7 from the NLRP3 inflammasome in mediating Ang II-induced hypertension, vascular damage, and immune activation. Both P2rx7-/- and Nlrp3-/- mice were protected from Ang II (490ng/kg/min) induced small artery endothelial dysfunction and had attenuated T cell activation. However, only P2rx7-/- mice were protected from Ang II-induced systolic blood pressure elevation. This study suggested that P2RX7-NLRP3 signalling is important for Ang II-induced T cell activation and endothelial dysfunction, but primarily P2RX7 contributes to Ang II-induced blood pressure elevation.The third study is a brief letter identifying a memory T lymphocyte subset with an unknown role in the context of hypertension. CD4+, CD8+ and γδ tissue-resident memory (TRM) cells increased up to 12-fold in the aortic PVAT of WT mice treated with Ang II. The expansion of TRM cells was inhibited by the genetic knockout or pharmacologic blockade of P2RX7.

Electronic reproduction.
Ann Arbor, Mich. :
ProQuest,
2023

Mode of access: World Wide Web

ISBN: 9798377672159Subjects--Topical Terms:

895384
Lymphocytes.
Index Terms--Genre/Form:

542853
Electronic books.

The Role of P2RX7 in Angiotensin II-Induced Hypertension and Cardiovascular Disease.
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502 $a Thesis (Ph.D.)--McGill University (Canada), 2022.
504 $a Includes bibliographical references
520 $a Hypertension affects more than one billion people worldwide and is the leading risk factor for burden of disease and mortality. It is associated with chronic low-grade inflammation and targets to diminish this low-grade inflammation are of interest. The purinergic receptor P2X7 (P2RX7) is activated by extracellular ATP and is a key regulator of inflammatory signalling, cellular death, and T lymphocyte development and function. Elevated plasma ATP levels have been observed in hypertensive patients, providing a potential mechanism for P2RX7 activation. Additionally, a hypomorphic polymorphism for P2X7 is correlated with a decreased risk for essential hypertension in Chinese post-menopausal women. The work in this thesis tests the hypothesis that P2RX7 mediates angiotensin (Ang) II-induced blood pressure elevation and cardiovascular injury by promoting the activation of innate and adaptive immune cells.In the first study, I assessed the contribution of P2RX7 to immune activation in hypertension and cardiovascular injury. Both P2rx7 knockout and P2RX7 antagonism attenuated Ang II (1000ng/kg/min) induced hypertension and small artery endothelial dysfunction. In addition, we found decreased infiltration of activated T cells into the aortic perivascular adipose tissue (PVAT) of Ang II-treated compared to wild-type (WT) control mice. Furthermore, WT mice treated with Ang II had an expansion of CD4+ and γδ T effector memory (TEM) cells in the spleen and aortic PVAT along with increased CD8+ TEM in the bone marrow. These changes were abrogated in P2rx7-/- mice or mice treated with a P2RX7 antagonist suggesting decreased immune activation in these mice. Neither P2rx7-/- mice nor P2RX7 antagonist-treated mice infused with Ang II were protected from cardiac dysfunction. In fact, Ang II-treated P2rx7-/- mice had reduced left ventricle fractional shortening and a dilated left ventricle compared to Ang II-treated WT mice, suggesting enhanced cardiac dysfunction. This study highlighted that P2rx7 knockout or P2RX7 antagonism attenuated Ang II-induced immune activation, and subsequent hypertension and vascular injury, but not cardiac dysfunction.In the second study, I aimed to delineate the role of P2RX7 from the NLRP3 inflammasome in mediating Ang II-induced hypertension, vascular damage, and immune activation. Both P2rx7-/- and Nlrp3-/- mice were protected from Ang II (490ng/kg/min) induced small artery endothelial dysfunction and had attenuated T cell activation. However, only P2rx7-/- mice were protected from Ang II-induced systolic blood pressure elevation. This study suggested that P2RX7-NLRP3 signalling is important for Ang II-induced T cell activation and endothelial dysfunction, but primarily P2RX7 contributes to Ang II-induced blood pressure elevation.The third study is a brief letter identifying a memory T lymphocyte subset with an unknown role in the context of hypertension. CD4+, CD8+ and γδ tissue-resident memory (TRM) cells increased up to 12-fold in the aortic PVAT of WT mice treated with Ang II. The expansion of TRM cells was inhibited by the genetic knockout or pharmacologic blockade of P2RX7.
520 $a L'hypertension touche plus d'un milliard de personnes dans le monde et constitue le principal facteur de risque de maladie et mortalite. Elle est associee a une inflammation chronique de bas niveau, et il pourrait etre interessant d'identifier des cibles diminuant cette inflammation. Le recepteur purinergique P2X7 (P2RX7) est un regulateur cle de la signalisation inflammatoire, de la mort cellulaire et du developpement et de la fonction des lymphocytes T. Des niveaux eleves d'ATP plasmatique ont ete observes chez des patients hypertendus, fournissant un mecanisme potentiel d'activation de P2RX7. De plus, un polymorphisme hypomorphe pour P2X7 est correle a une diminution du risque d'hypertension essentielle chez les femmes menopausees chinoises. Les travaux rapportes dans cette these testent l'hypothese selon laquelle P2RX7 medie l'elevation de la tension arterielle et les lesions cardiovasculaires induites par l'angiotensine (Ang) II via l'activation des cellules immunitaires innees et adaptatives.Dans la premiere etude, nous avons evalue la contribution de P2RX7 dans l'activation immunitaire dans l'hypertension et les lesions cardiovasculaires. L'inactivation de P2rx7 et l'antagonisme de P2RX7 ont reduit l'elevation de la tension arterielle et le dysfonctionnement endothelial des petites arteres induits par l'Ang II (1000 ng/kg/min). De plus, nous avons constate une diminution de l'infiltration des lymphocytes T actives dans le tissu adipeux perivasculaire (TAPV) aortique des souris traitees avec l'Ang II par rapport aux souris sauvages controles. En plus, les souris sauvages traitees avec l'Ang II presentaient une expansion des cellules T memoire effectrices (TEM) CD4+ et γδ dans la rate et le TAPV aortique, ainsi qu'une augmentation des cellules TEM CD8+ dans la moelle osseuse. Ces augmentations ont ete abrogees chez les souris P2rx7-/- ou les souris traitees avec un antagoniste P2RX7 suggerant une diminution de l'activation immunitaire chez ces souris. Ni les souris P2rx7-/- ni les souris traitees avec un antagoniste P2RX7 infusees avec l'Ang II n'etaient protegees contre le dysfonctionnement cardiaque. En fait, les souris P2rx7-/- traitees avec l'Ang II presentaient une diminution de la fraction de raccourcissement du ventricule gauche et un ventricule gauche dilate comparativement aux souris sauvages traitees avec l'Ang II suggerant une dysfonction cardiaque exacerbee. Cette etude a mis en evidence que le knock-out de P2rx7ou l'antagonisme de P2RX7 attenuait l'activation immunitaire induite par l'Ang II et l'hypertension et les lesions vasculaires qui en resultaient, mais pas le dysfonctionnement cardiaque.Dans la deuxieme etude, nous avons cherche a determiner les contributions relatives de P2RX7 et d'une composante de l'inflammasome, NLRP3 ("NOD-like receptor family, pyrin domain containing 3"), dans l'hypertension et les lesions vasculaires induites par l'Ang II. Les souris P2rx7-/- et Nlrp3-/- etaient toutes deux protegees du dysfonctionnement endothelial des petites arteres et presentaient une activation attenuee des lymphocytes T induite par l'Ang II (490 ng/kg/min). Cependant, seules les souris P2rx7-/- etaient protegees contre l'elevation de la tension arterielle systolique induite par l'Ang II.
533 $a Electronic reproduction. $b Ann Arbor, Mich. : $c ProQuest, $d 2023
538 $a Mode of access: World Wide Web
650 4 $a Lymphocytes. $3 895384
650 4 $a Medicine. $3 641104
650 4 $a Hypertension. $3 825110
650 4 $a Immunology. $3 611031
655 7 $a Electronic books. $2 lcsh $3 542853
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773 0 $t Dissertations Abstracts International $g 84-10B.
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=30346964 $z click for full text (PQDT)