application) The renin-angiotensin system (RAS) plays an integral role in cardiovascular homeostasis through its effects on vascular tone and volume, and pharmacological interruption of this system has found widespread clinical application. Independent of the effects of the RAS on blood pressure, activation of this system has been responsible for this association, the PI has focused on the effects of the RAS on the plasminogen activator system, which serves as one of the major endogenous defense mechanisms against intravascular thrombosis and also plays an important role in vascular and tissue remodeling. Vascular fibrinolytic balance is, to a large part, determined by the competing effects of plasminogen activators and plasminogen activator inhibitor-1 (PAI-1), both of which are locally synthesized in the blood vessel wall, and in particular, the vascular endothelium. The central hypothesis of this proposal is that a major component of the vascular toxicity brought on by activation of the RAS is derived from the deleterious effects of angiotensin on fibrinolytic balance. Over the past three years, this grant has supported research that has helped to define the strategic role of angiotensin converting enzyme in regulating vascular fibrinolytic balance. The PI has also defined a role for angiotensin in promoting endothelial PAI-1 expression, an effect that appears to be mediated by the binding of the hexapeptide angiotensin II (3-8) (Angiotensin IV) to a non-classical angiotensin (AT4) receptor. This proposal is designed to extend our understanding of the biology of the endothelial AT4 receptor, and to characterize the effects of angiotensin on PAI-1 expression in vivo.
The specific aims of this proposal are the following: 1) to characterize the mechanisms through which Ang IV regulates endothelial gene expression in vitro; 2) to compare the effects of Ang II vs Ang IV on the tissue-specific expression of PAI-1 in vivo; and 3) to study the effects of AT4 receptor agonists and antagonists on the development of vascular lesions in genetically altered mice. It is anticipated that these studies will generate important and relevant information regarding the interactions of the RAS, the vascular endothelium, and fibrinolysis. Furthermore, this project may contribute to our understanding of the regulation of two systems that play vital roles in cardiovascular homeostasis, and thus may improve our ability to prevent and treat ischemic cardiovascular disease.
| Flevaris, Panagiotis; Khan, Sadiya S; Eren, Mesut et al. (2017) Plasminogen Activator Inhibitor Type I Controls Cardiomyocyte Transforming Growth Factor-? and Cardiac Fibrosis. Circulation 136:664-679 |
| Rai, Rahul; Verma, Suresh K; Kim, David et al. (2017) A novel acetyltransferase p300 inhibitor ameliorates hypertension-associated cardio-renal fibrosis. Epigenetics 12:1004-1013 |
| Yahata, Takashi; Ibrahim, Abd Aziz; Muguruma, Yukari et al. (2017) TGF-?-induced intracellular PAI-1 is responsible for retaining hematopoietic stem cells in the niche. Blood 130:2283-2294 |
| Eren, Mesut; Place, Aaron T; Thomas, Paul M et al. (2017) PAI-1 is a critical regulator of FGF23 homeostasis. Sci Adv 3:e1603259 |
| Rai, Rahul; Ghosh, Asish K; Eren, Mesut et al. (2017) Downregulation of the Apelinergic Axis Accelerates Aging, whereas Its Systemic Restoration Improves the Mammalian Healthspan. Cell Rep 21:1471-1480 |
| Khan, Sadiya S; Shah, Sanjiv J; Klyachko, Ekaterina et al. (2017) A null mutation in SERPINE1 protects against biological aging in humans. Sci Adv 3:eaao1617 |
| Afzal, Muhammad Zeeshan; Gartz, Melanie; Klyachko, Ekaterina A et al. (2017) Generation of human iPSCs from urine derived cells of a non-affected control subject. Stem Cell Res 18:33-36 |
| Vaughan, Douglas E; Rai, Rahul; Khan, Sadiya S et al. (2017) Plasminogen Activator Inhibitor-1 Is a Marker and a Mediator of Senescence. Arterioscler Thromb Vasc Biol 37:1446-1452 |
| Afzal, Muhammad Zeeshan; Gartz, Melanie; Klyachko, Ekaterina A et al. (2017) Generation of human iPSCs from urine derived cells of patient with a novel heterozygous PAI-1 mutation. Stem Cell Res 18:41-44 |
| Bautista-Niño, Paula K; Portilla-Fernandez, Eliana; Vaughan, Douglas E et al. (2016) DNA Damage: A Main Determinant of Vascular Aging. Int J Mol Sci 17: |
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