The long-term goal of our research program is to elucidate microRNA mechanisms that alter normal regulation of genes in response to overactivity of the angiotensin II type 1 receptor (AT1R). Angiotensin II (AngII) is the classical mediator of the effects of the renin-angiotensin system on the cardiovascular homeostasis. This receptor regulates gene expression targeted by the AT1R-blockers (ARB), a widely used class of anti- hypertensive drugs that are currently in trial for the prevention of vascular, renal and cardiac hypertrophy, aortic aneurism, vascular fibrosis, breast tumor growth and angiogenesis. Inhibition of AT1R in renal, vascular and cardiac cells by ARBs is protective, but the activation o the receptor causes hypertrophy and progressive fibrosis of the respective organs/tissues. In preliminary studies we have discovered that chronic activation of AT1R deregulates gene expression through both transcriptional and post-transcriptional mechanisms. To directly link deregulation of gene expression to hypertrophy and fibrosis, we profiled mRNA and microRNA (miRNA) expression in the AT1R TG mice aorta, heart, and in HL1-AT1R (cardiomyocyte) and the VSMC-AT1R cell lines. Typical transcriptional and miRNA regulatory mechanisms are significantly altered in all of the experimental models. In a separate study, we have shown significantly altered miRNA expression profile in dilated cardiomyopathy human hearts. The altered miRNAs target gene networks that do account for compensatory remodeling in human heart failure. These novel studies suggest that mRNA and miRNA profiles, together, contribute to AT1R biology in health and disease. Our current proposal will focus on the novel roles of two AT1R-modulated microRNAs: miR-205 and mir-483.
Three Specific Aims are proposed to test the hypothesis that specific transcriptional and post-transcriptional regulatory mechanisms tilt the dynamics of typical hypertrophy and fibrosis signaling towards a disease connotation. They are: (i) to determine miR-205 mechanisms which alter critical signaling components in models of hypertrophy and fibrosis, (ii) to determine the miR-483 mechanism of up-regulation of the rennin angiotensin system, and (iii) to determine the AT1R regulated mechanisms of biogenesis and the stability of miR-205 and miR-483. If the AT1R activity is not regulated properly, AngII stimulus becomes chronic and can damage the tissue, as well as contribute to chronic disorders of blood vessels, kidney and heart. A clear understanding of these mechanisms is important to improve the therapeutic application of ARBs. These proposed studies will advance our knowledge of the biology of AT1R signaling causing hypertrophy and fibrosis. There is potential relevance for this knowledge base in understanding normal functioning aorta, vasculature in brain, kidney and heart, as well as the pathology of heart failure, atherosclerosis and aortic aneurysm.

Public Health Relevance

The type 1 receptor for the vasoactive hormone AngII is a regulator of gene expression targeted by the angiotensin receptor blocker (ARB) class of anti-hypertensive drugs. Inhibition of this AngII receptor in renal and cardiovascular cells by ARBs is protective, but activation of the receptor causes hypertrophy and fibrosis. We have discovered that AngII receptor activates a novel transcription program that includes modulation of microRNA expression. In this proposal we will be investigating the novel microRNA pathways by which AngII receptor regulates cellular hypertrophy and fibrosis. These studies are relevant for understanding normal functioning aorta, vasculature in brain, kidney and heart, as well as the pathology of HF, atherosclerosis and aortic aneurysm. These studies are necessary to understand mechanisms of cardiovascular disease progression, and to identify new drug targets for intervention. Hypertensive and hypertrophic disease remains a major public health concern and adequate treatment for reversal of these diseases is currently lacking.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL115964-02
Application #
8485661
Study Section
Special Emphasis Panel (ZRG1-VH-D (02))
Program Officer
Galis, Zorina S
Project Start
2012-07-01
Project End
2016-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
2
Fiscal Year
2013
Total Cost
$373,660
Indirect Cost
$135,660
Name
Cleveland Clinic Lerner
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
135781701
City
Cleveland
State
OH
Country
United States
Zip Code
44195
Tirupula, Kalyan C; Desnoyer, Russell; Speth, Robert C et al. (2014) Atypical signaling and functional desensitization response of MAS receptor to peptide ligands. PLoS One 9:e103520
Kemp, Jacqueline R; Unal, Hamiyet; Desnoyer, Russell et al. (2014) Angiotensin II-regulated microRNA 483-3p directly targets multiple components of the renin-angiotensin system. J Mol Cell Cardiol 75:25-39