Atherosclerotic and hypertensive cardiovascular diseases (CVDs) are major causes of morbidity and mortality and a severe strain on our healthcare system. The peptide hormone Angiotensin II (Ang II) plays a major role in these pathologies due to its vasoconstrictive, pro-oxidant, -growth and -inflammatory properties in target cells such as vascular smooth muscle cells (VSMC). Several studies have documented the biochemical and signaling mechanisms of Ang II actions via the type 1 receptor (AT1R) in VSMC. However, the precise nuclear epigenetic mechanisms involved in AngII induced transcriptional regulation of pathological genes are not clear. It is increasingly recognized that profound alterations in chromatin structure, including changes in epigenetic posttranslational modifications (PTMs) of histones, such as Histone H3 -lysine methylation (H3Kme) can regulate the "active" or "inactive" state of genes. Recent evidence has also demonstrated the key roles of microRNAs (miRs) in gene regulation by posttranscriptional mechanisms. Our goal is to evaluate such epigenetic and miR mechanisms in Ang II actions in order to unravel new therapeutic targets. We hypothesize that the dysregulation of histone H3Kme and aberrant expression of key miRs contribute to Ang II induced VSMC dysfunction associated with various CVDs. This will be tested via 3 Specific Aims using state-of-the-art genome-wide profiling and bioinformatics approaches in cell culture along with relevant mouse models.
Specific Aim 1 is to perform epigenome profiling of key chromatin histone H3Kme marks in VSMC treated with and without Ang II, evaluate the chromatin enzymes regulating these marks, and then their functional roles in VSMC.
Specific Aim 2 is to profile the miR signatures in VSMC in response to Ang II and then determine the functional relevance of key differentially expressed miRs.
Specific Aim 3 is to evaluate specific mouse models of increased Ang II action in order to determine the in vivo relevance of the epigenetic marks and miRs uncovered in Aims 1 and 2. When completed, the proposed work will yield novel new data describing the epigenetic and miR profiles of VSMC under Ang II treated conditions, and also bring in new next generation genome sequencing technologies to the field of vascular biology. The results can increase our understanding of Ang II actions, and identify new targets that might be developed as clinical therapies for CVDs such as hypertension and atherosclerosis.

Public Health Relevance

Despite the availability of several therapies, the rates of cardiovascular diseases such as atherosclerosis and hypertension are soaring. Furthermore, these vascular complications are significantly higher in the diabetic population. Together, they are a severe drain on our healthcare resources. Since Angiotensin II is a major player in these pathologies, we propose to identify novel new epigenetic and micro-RNA based mechanisms responsible for Angiotensin II- induced expression of pathologic genes in vascular smooth muscle cells. We will use state-of- the-art profiling technologies to achieve our Specific Aims and thereby advance our long-term goal to identify new mechanisms and drug targets for cardiovascular diseases.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL106089-02
Application #
8206457
Study Section
Vascular Cell and Molecular Biology Study Section (VCMB)
Program Officer
OH, Youngsuk
Project Start
2011-01-01
Project End
2015-12-31
Budget Start
2012-01-01
Budget End
2012-12-31
Support Year
2
Fiscal Year
2012
Total Cost
$415,000
Indirect Cost
$165,000
Name
City of Hope/Beckman Research Institute
Department
Type
DUNS #
027176833
City
Duarte
State
CA
Country
United States
Zip Code
91010
Reddy, Marpadga A; Zhang, Erli; Natarajan, Rama (2015) Epigenetic mechanisms in diabetic complications and metabolic memory. Diabetologia 58:443-55
Miao, Feng; Chen, Zhuo; Genuth, Saul et al. (2014) Evaluating the role of epigenetic histone modifications in the metabolic memory of type 1 diabetes. Diabetes 63:1748-62
Reddy, Marpadga A; Chen, Zhuo; Park, Jung Tak et al. (2014) Regulation of inflammatory phenotype in macrophages by a diabetes-induced long noncoding RNA. Diabetes 63:4249-61
Leung, Amy; Parks, Brian W; Du, Juan et al. (2014) Open chromatin profiling in mice livers reveals unique chromatin variations induced by high fat diet. J Biol Chem 289:23557-67
Reddy, Marpadga A; Sumanth, Putta; Lanting, Linda et al. (2014) Losartan reverses permissive epigenetic changes in renal glomeruli of diabetic db/db mice. Kidney Int 85:362-73
Leung, Amy; Natarajan, Rama (2014) Noncoding RNAs in vascular disease. Curr Opin Cardiol 29:199-206
Kato, Mitsuo; Castro, Nancy E; Natarajan, Rama (2013) MicroRNAs: potential mediators and biomarkers of diabetic complications. Free Radic Biol Med 64:85-94
Leung, Amy; Natarajan, Rama (2013) Forgetting to switch off SMAD2 in aneurysmal disease. Circ Res 113:843-5
Leung, Amy; Trac, Candi; Jin, Wen et al. (2013) Novel long noncoding RNAs are regulated by angiotensin II in vascular smooth muscle cells. Circ Res 113:266-78
Reddy, Marpadga A; Tak Park, Jung; Natarajan, Rama (2013) Epigenetic modifications in the pathogenesis of diabetic nephropathy. Semin Nephrol 33:341-53

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