2 Exploring the transcriptomic profiles of phenylephrine-induced cardiac myocyte hypertrophy following phosphodiesterase 5 inhibition

<h3>Introduction</h3> Cardiac hypertrophy is the main risk factor for heart failure. Despite protecting against left ventricular hypertrophy, the exact molecular mechanisms of how phosphodiesterase 5 (PDE5) inhibitors work remain unclear. This study explores the protective effect of PDE5 inhibition on cardiac myocyte hypertrophy and its impact on the transcriptomic profile of phenylephrine (PE)-induced hypertrophy¹ in neonatal rat ventricular myocytes (NRVM). <h3>Methods</h3> Following NRVM isolation from Wistar rats, 4 treatment groups were developed: Control (DMSO vehicle), 30 μM PE, 50 nM tadalafil (Tad), and 30 μM PE+50 nM Tad. NRVM were exposed to PE treatment for 96 hours, and cells were harvested on day 8 post-isolation. The cells were imaged with a confocal microscope or subjected to RNA extraction. RNA integrity number (RIN) was performed prior to RNA sequencing (RNA-seq). <h3>Results</h3> PDE5 inhibition prevents cardiac myocyte hypertrophy following PE exposure (p &lt; 0.0001). The RIN for all samples was 10.0, indicating the highest quality of RNA. Two common differential expression genes were identified between PE vs control and Tad vs PE comparison: Transcription factor EB (TFEB) was shown to be upregulated in the PE vs control group and downregulated in the Tad vs PE group, while lysine (K)-specific demethylase 1A (KDM1A) was downregulated in the PE vs control group and upregulated in the Tad vs PE group. Overexpression of TFEB in cardiac myocytes leads to cardiac hypertrophy,² whereas a decreased level of KDM1A is related to pressure overload-induced cardiac remodelling and fibrosis.³ <h3>Conclusion</h3> PDE5 inhibition reduces cardiac myocyte size via intricate molecular mechanisms where it downregulates TFEB gene expression and upregulates KDM1A, which is crucial for gene regulation in cardiac myocytes. These results suggest that PDE5 inhibition could protect against cardiac hypertrophy by targeting specific molecular signalling pathways involved in gene expression regulation. <h3>References</h3> Geraets IME, Coumans WA, Strzelecka A, Schönleitner P, Antoons G, Schianchi F, <i>et al</i>. Metabolic interventions to prevent hypertrophy-induced alterations in contractile properties in vitro. <i>Int J Mol Sci.</i> 2021;<b>22</b>(7):3620. Huo J, An Q, Chen X, Qin Z, Gao E, Chen D, <i>et al</i>. Cardiac-specific inactivation of LSD1 in mice leads to myocardial hypertrophy and heart failure. <i>JMCC.</i> 2020;<b>140</b>:45. Kenny HC, Weatherford ET, Collins GV, Allamargot C, Gesalla T, Zimmerman K, <i>et al</i>. Cardiac specific overexpression of transcription factor EB (TFEB) in normal hearts induces pathologic cardiac hypertrophy and lethal cardiomyopathy. <i>bioRxiv.</i> https://doi.org/10.1101/2021.02.16.431474