Role of snoRNAs in regulation of cardiac hypertrophy

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ABSTRACT Pathologic cardiac hypertrophy is a common feature in many cardiovascular diseases, such as hypertension, aortic stenosis, ischemic heart disease, and heart failure. As such, the regulation of cardiomyocyte hypertrophy has been extensively studied, and it is regulated, in part, by reactive oxygen species (ROS). Despite this, there have been no successful clinical treatments that specifically target ROS or cardiovascular oxidative stress as a pathologic mechanism. The aim of this proposal is to investigate a novel and drug-targetable pathway that regulates ROS and oxidative stress via non-coding RNAs (ncRNA) known as snoRNA (small nucleolar RNA). These short ncRNA canonically act as “guides” for enzymes that catalyze nucleotide modifications on target RNAs. Recently, four snoRNAs from the Rpl13a locus have been identified as unexpected regulators of ROS and oxidative stress, both in vitro and in vivo. Since cardiac hypertrophy is regulated by ROS, we hypothesized that the Rpl13a snoRNAs would be important for this process. Preliminary data now shows that mice lacking the Rpl13a snoRNAs are, in fact, resistant to hypertrophy and pathologic cardiac remodeling in the setting of pressure overload from transverse aortic constriction. Moreover, the loss of these snoRNAs also results in unusually small hearts in young mice, suggesting that the Rpl13a snoRNAs may be general regulators of cardiomyocte size. The research proposed in this application will build on these important physiologic findings in order to understand the mechanisms by which the Rpl13a snoRNAs influence ROS, oxidative stress, and cardiac cell size. Specifically, Aim 1 will identify and validate transcriptional networks that are regulated by the Rpl13a snoRNAs, using in vitro and in vivo models of cardiomyocyte hypertrophy combined with RNA-seq to quantitatively assess both coding and non-coding RNAs. Aim 2 will specifically examine the relationship between Nox4 and the Rpl13a snoRNAs in the ROS-mediated regulation of cardiomyocyte size, both for the determination of normal cell size and hypertrophy. The preliminary data generated here will be used to support a larger R01 application to directly address the mechanisms by which snoRNAs regulate ROS and oxidative stress in relation to cardiac cell size and hypertrophy.