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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Vascular Cell and Molecular Biology Study Section (VCMB)
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OH, Youngsuk
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Beckman Research Institute/City of Hope
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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
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