Cardiovascular diseases (CVDs) such as atherosclerosis and hypertension are the leading causes of morbidity and mortality in our community. Furthermore these vascular complications are accelerated in the diabetic population. Epigenetic mechanisms have been implicated in several common human diseases, including CVDs, due to the influence of the environment which can affect epigenetic states. Evidence shows that the hormone Angiotensin II (Ang II) is a major player in the pathologies of hypertension and atherosclerosis due to its vasoconstrictive, pro-inflammatory, pro-oxidant, and growth promoting effects in target cells such as vascular smooth muscle cells (VSMC). During the previous funding period, we reported the first functional roles for epigenetic chromatin histone modifications and non-coding RNAs in mediating some of these deleterious actions of Ang II in VSMCs. In addition, our new preliminary data show that Ang II can regulate specific novel long non-coding RNAs (lncRNAs), and enhancers in VSMCs that modulate the expression of target genes associated with VSMC inflammation and dysfunction. Despite these advances, the functions of specific lncRNAs and their subtle interactions with other epigenetic factors like enhancers to modulate Ang II-induced gene expression are still not fully understood. Furthermore, the roles of enhancers, superenhancers and specific lncRNAs in Ang II-mediated VSMC dysfunction and related CVDs are not known. Our central hypothesis is that dynamic control of key lncRNAs and VSMC- specific enhancers/superenhancers, as well as epigenetic cross-talk among these factors, contribute to Ang II-induced VSMC dysfunction associated with CVDs. This will be tested through 3 Specific Aims.
In Specific Aim 1, we will examine the molecular mechanisms of regulation and functional roles of two novel lncRNAs that we found to be induced by Ang II in VSMCs.
In Specific Aim 2, we will define the roles of Ang II-regulated enhancers and superenhancers in the expression of Ang II-regulated genes involved in VSMC functions.
In Specific Aim 3, the in vivo expression and functional roles of the two lncRNAs and candidate enhancers/SEs will be examined in mouse models of Ang II induced vascular dysfunction and atherosclerosis. This study examines several new concepts and uses innovative platforms along with functional in vivo models to gain novel insights into VSMC regulatory networks. The results and can have potentially far reaching clinical and therapeutic implications for CVDs.

Public Health Relevance

Cardiovascular diseases such as atherosclerosis and hypertension are highly prevalent in our community and a major cause of morbidity and mortality. Together, they are a severe drain on our healthcare resources. Furthermore currently available drugs for these disorders are not fully efficacious in many patients. Since Angiotensin II is a major player in these vascular pathologies, we propose to identify novel new epigenetic and RNA based mechanisms responsible for Angiotensin II-induced vascular dysfunction and expression of pathologic genes in vascular smooth muscle cells. The results of these studies could lead to the identification of much needed newer and better therapeutic targets for cardiovascular diseases.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL106089-08
Application #
9623365
Study Section
Vascular Cell and Molecular Biology Study Section (VCMB)
Program Officer
OH, Youngsuk
Project Start
2011-01-01
Project End
2020-12-31
Budget Start
2019-01-01
Budget End
2019-12-31
Support Year
8
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Beckman Research Institute/City of Hope
Department
Type
DUNS #
027176833
City
Duarte
State
CA
Country
United States
Zip Code
91010
Das, Sadhan; Reddy, Marpadga A; Senapati, Parijat et al. (2018) Diabetes Mellitus-Induced Long Noncoding RNA Dnm3os Regulates Macrophage Functions and Inflammation via Nuclear Mechanisms. Arterioscler Thromb Vasc Biol 38:1806-1820
Leung, Amy; Natarajan, Rama (2018) Long Noncoding RNAs in Diabetes and Diabetic Complications. Antioxid Redox Signal 29:1064-1073
Das, Sadhan; Zhang, Erli; Senapati, Parijat et al. (2018) A Novel Angiotensin II-Induced Long Noncoding RNA Giver Regulates Oxidative Stress, Inflammation, and Proliferation in Vascular Smooth Muscle Cells. Circ Res 123:1298-1312
Deshpande, Supriya; Abdollahi, Maryam; Wang, Mei et al. (2018) Reduced Autophagy by a microRNA-mediated Signaling Cascade in Diabetes-induced Renal Glomerular Hypertrophy. Sci Rep 8:6954
Leung, Amy; Amaram, Vishnu; Natarajan, Rama (2018) Linking diabetic vascular complications with LncRNAs. Vascul Pharmacol :
Gangwar, Roopesh S; Rajagopalan, Sanjay; Natarajan, Rama et al. (2018) Noncoding RNAs in Cardiovascular Disease: Pathological Relevance and Emerging Role as Biomarkers and Therapeutics. Am J Hypertens 31:150-165
Rosen, Evan D; Kaestner, Klaus H; Natarajan, Rama et al. (2018) Epigenetics and Epigenomics: Implications for Diabetes and Obesity. Diabetes 67:1923-1931
Das, Sadhan; Senapati, Parijat; Chen, Zhuo et al. (2017) Regulation of angiotensin II actions by enhancers and super-enhancers in vascular smooth muscle cells. Nat Commun 8:1467
Reddy, Marpadga A; Das, Sadhan; Zhuo, Chen et al. (2016) Regulation of Vascular Smooth Muscle Cell Dysfunction Under Diabetic Conditions by miR-504. Arterioscler Thromb Vasc Biol 36:864-73
Kato, Mitsuo; Wang, Mei; Chen, Zhuo et al. (2016) An endoplasmic reticulum stress-regulated lncRNA hosting a microRNA megacluster induces early features of diabetic nephropathy. Nat Commun 7:12864

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