Effect of preventive training in cardiac transcriptoma in rats with pulmonary hypertension

Abstract

Abstract Funding Acknowledgements Type of funding sources: None. Introduction Pulmonary hypertension (PH) is a progressive disease characterized by elevated right ventricular afterload, vascular remodeling, right ventricular hypertrophy and dysfunction, and ultimately heart failure. Physical exercise has been recognized as a treatment for this condition. Although different mechanisms have been proposed to explain PH development, the influence of preventive exercise training interventions onset of pulmonary hypertension in right ventricular hypertrophy is underexplored. Purpose Analyze the effect of preventive training in global gene expression profiling of right ventricular in PH from rats. Methods Twenty-four male Wistar rats (206-220 g) were divided into three four groups (n=8/group): S, sedentary control; SPH, sedentary pulmonary hypertension; and TPH, trained pulmonary hypertension group. The preventive training protocol was performed on a treadmill for 13 weeks, five times/week. Cardiac hypertrophy by PH was experimentally induced by a single intraperitoneal injection (60 mg/kg) of monocrotaline after the protocol training. The S were injected with saline solution. The rats were evaluated 28 days after monocrotaline administration, in the early stage of the PH. Left ventricle weight, right ventricle weight, and atrium weight normalized by body weight were used as indexes of heart hypertrophy. Gene expression profiling was performed using the Rat Gene ST Array platform. To further understand the biological relevance of differential expressed genes, we performed a functional enrichment analysis in the context of the gene ontology (biological process, molecular function, and cellular component) and interaction networks (KEGG, Reactome, Wikipathways and BioPlanet). Results Through the analysis, the HP group had cardiac hypertrophy, and the training mitigated this change p< 0.05. Global gene expression profiling identified 687 differentially expressed genes (S vs. SPH), in the hypertrophy right ventricular during PH, and when compared to preventive training, 91 genes were dysregulated (SPH vs TPH). Gene ontology analysis on expression profiling data revealed alteration on genes that regulate the inflammatory process, muscle growth, metabolic processes, cell death, and ion regulation comparison between SPH vs. TPH The genes that were altered in the hypertrophy phase of PH and modified by the exercise were platelet alpha granule lumen (genes Fgg and Qsox1), NAD + binding (gene Cryl1), positive regulation of cAMP-mediated signaling (gene Cxcl11), positive regulation of macrophage differentiation (Il34 gene), mRNA cleavage (Cstf3 gene), negative regulation of transporter activity (Wwp2 gene), regulation of respiratory system process (Mtg2 gene) p< 0.05. Conclusion Preventive training influences changes in cardiac gene expression profile in the hypertrophy stage of PH. New genes have been identified, and these could be biomarkers and potential therapeutic targets in the early stage of PH.