Angiotensin II (Ang II) has recently become recognized as a powerful pro-inflammatory mediator. Although originally appreciated for its critical role in regulating blood pressure, this peptide hormone is now known to stimulate inflammatory pathways in numerous tissues, including the heart and arteries. Chronic exposure to Ang II may then lead to a variety of pathologic conditions related to a heightened inflammatory state. Perhaps the best example is in muscular arteries, where Ang II contributes to the development of atherosclerosis by stimulating the recruitment of macrophages and other inflammatory cells, stimulating smooth muscle proliferation and activation, and promoting endothelial dysfunction. The principal receptor for Ang II (AT1R) is a member of the G protein-coupled receptor superfamily. Numerous signaling pathways are initiated following ligand activation of this receptor, but stimulation of the NF-:B transcription factor appears to underlie most of the pro-inflammatory effects of Ang II. Importantly, while activation of protein kinase C (PKC) is a prerequisite for this effect, very little is known about the intermediate steps that bridge Ang II-dependent PKC activation with the eventual stimulation of NF-:B. However, our preliminary data now reveal a molecular link to explain this phenomenon. Our data indicate that a scaffolding protein (CARMA3) serves to integrate an upstream signal from PKC with the downstream effector proteins, Bcl10 and MALT1, which together stimulate a canonical pathway for NF-:B activation. We propose to explore the physiologic and biochemical implications of this signaling pathway through 4 aims: (1) Identify the molecular mechanism by which the AT1 receptor communicates with CARMA3. (2) Identify the molecular mechanism by which the IKK complex is activated following Ang II stimulation. (3) Test the role of CARMA3, Bcl10, and MALT1 in mediating Ang II-dependent inflammatory responses in endothelial and vascular smooth muscle cells. (4) Test the role of CARMA3 in mediating Ang II-dependent cardiovascular pathology, through analysis of CARMA3 knockout mice. Project Relevance: Ang II-dependent hypertension is a major contributing factor to cardiovascular disease. Understanding the pro-inflammatory, intracellular signaling events activated by Ang II is critical for our ability to eventually control the adverse effects of Ang II. Detailed knowledge of these signaling events will allow for the rational design of pharmacologic agents to target these events.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL082914-02
Application #
7555362
Study Section
Vascular Cell and Molecular Biology Study Section (VCMB)
Program Officer
Tolunay, Eser
Project Start
2008-02-01
Project End
2013-01-31
Budget Start
2009-02-01
Budget End
2010-01-31
Support Year
2
Fiscal Year
2009
Total Cost
$352,772
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Pathology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Klei, Linda R; Hu, Dong; Panek, Robert et al. (2016) MALT1 Protease Activation Triggers Acute Disruption of Endothelial Barrier Integrity via CYLD Cleavage. Cell Rep 17:221-232
Markó, Lajos; Henke, Norbert; Park, Joon-Keun et al. (2014) Bcl10 mediates angiotensin II-induced cardiac damage and electrical remodeling. Hypertension 64:1032-9
Rosebeck, S; Rehman, A O; Apel, I J et al. (2014) The API2-MALT1 fusion exploits TNFR pathway-associated RIP1 ubiquitination to promote oncogenic NF-?B signaling. Oncogene 33:2520-30
Van Beek, Matthew; Oravecz-Wilson, Katherine I; Delekta, Phillip C et al. (2012) Bcl10 links saturated fat overnutrition with hepatocellular NF-kB activation and insulin resistance. Cell Rep 1:444-52
Rosebeck, Shaun; Rehman, Aasia O; Lucas, Peter C et al. (2011) From MALT lymphoma to the CBM signalosome: three decades of discovery. Cell Cycle 10:2485-96
McAllister-Lucas, Linda M; Baens, Mathijs; Lucas, Peter C (2011) MALT1 protease: a new therapeutic target in B lymphoma and beyond? Clin Cancer Res 17:6623-31
Rosebeck, Shaun; Lucas, Peter C; McAllister-Lucas, Linda M (2011) Protease activity of the API2-MALT1 fusion oncoprotein in MALT lymphoma development and treatment. Future Oncol 7:613-7
Okawada, Manabu; Koga, Hiroyuki; Larsen, Scott D et al. (2011) Use of enterally delivered angiotensin II type Ia receptor antagonists to reduce the severity of colitis. Dig Dis Sci 56:2553-65
Rosebeck, Shaun; Madden, Lisa; Jin, Xiaohong et al. (2011) Cleavage of NIK by the API2-MALT1 fusion oncoprotein leads to noncanonical NF-kappaB activation. Science 331:468-72
McAllister-Lucas, Linda M; Jin, Xiaohong; Gu, Shufang et al. (2010) The CARMA3-Bcl10-MALT1 signalosome promotes angiotensin II-dependent vascular inflammation and atherogenesis. J Biol Chem 285:25880-4

Showing the most recent 10 out of 13 publications