Date of Award

2013

Degree Type

Dissertation

Department

Biological, Geological and Environmental Sciences

First Advisor

Karnik, Sadashiva

Subject Headings

Genomes, Renin-angiotensin system, Small interfering RNA, Vascular smooth muscle, genome-wide expression profiling Renin-Angiotensin System AngII AT1R microRNA vascular smooth muscle phenotypic switching

Abstract

Renin-angiotensin system (RAS) activation and phenotypic modulation of vascular smooth muscle cells (VSMCs) are common characteristics associated with human diseases, such as pulmonary hypertension, atherosclerosis and stroke. While elevation of the RAS hormone product, angiotensin II (AngII) is a well-established risk in these diseases the mechanism of activation of RAS and modulation of VSMC phenotype by AngII is vague, suggesting that novel global regulators may mediate the risk by AngII. MicroRNAs (miRNAs) represent one such class of potential global regulators. MiRNAs are small (̃22 nt), endogenous, non-coding RNAs that act as post-transcriptional regulators of physiological processes. MiRNAs primarily function by binding to complementary target sites in the 3'-untranslated regions (3'-UTR) of mRNAs, causing translational repression and/or mRNA destabilization. To elucidate the global miRNA expression profile following chronic Angiotensin II Type 1 Receptor (AT1R) activation by AngII, we performed microarray analysis in 23 biological and technical replicates derived from humans, rats and mice. We pharmacologically distinguished the AT1R-regulated miRNA profiles by comparing technical replicates treated with the specific AT1R-blocker, losartan and biological replicates following chronic AT2R activation by AngII. Thirty-two miRNAs are AngIIregulated universally. Most other miRNAs are regulated in a treatment- or speciesspecific manner. A few miRNAs are unique to specific cell types. We have previously shown that a single miRNA can have multiple targets,potentially providing simultaneous regulation of the genes involved in a physiological pathway and accounting for a complex phenotype, such as human heart failure (JBC 284: 27487-27499). In the current study, we explored the extent to which AngII/AT1Rregulated miRNAs contribute to maintenance of RAS homeostasis and phenotypic modulation of VSMCs. A distinct AngII-regulated miRNA expression pattern emerged in the human and rat VSM cell lines in th

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