Effect of sacubitril-valsartan on transcriptomic changes in lung tissue of spontaneously hypertensive rats: a multi-omics study based on RNA-Seq transcriptome analysis.

Abstract

Background: Hypertension, a prevalent cardiovascular disorder, exerts detrimental effects on the respiratory system. However, the underlying mechanisms remain incompletely elucidated.

Methods: We conducted comparative transcriptomic profiling via RNA sequencing (RNA-seq) of lung tissues from spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) controls. Additionally, we assessed the effects of angiotensin receptor blocker (ARB) and angiotensin receptor-neprilysin inhibitor (ARNI) interventions on mRNA and protein expression profiles in SHR pulmonary tissue using integrated omics approaches.

Results: Core differentially expressed genes (DEGs) identified in SHR versus WKY comparisons included Nuf2 and Cenpa, with significant enrichment in the PI3K/AKT signaling pathway. In SHR versus ARB-treated cohorts, hub genes Ccnb2 and Mad2l1 demonstrated primary pathway enrichment in cell cycle regulation and human T-cell leukemia virus 1 infection. ARNI intervention yielded distinct hub genes (Gzma, Icam1) enriched in PI3K/AKT signaling and extracellular matrix (ECM)-receptor interactions. Proteomic analysis confirmed concordant expression patterns for EGFR and JUN proteins with transcriptomic findings.

Conclusion: ARB and ARNI therapies mitigate hypertension-induced pulmonary damage through divergent molecular mechanisms, with PI3K/AKT signaling and ECM-receptor interactions serving as central regulatory hubs in this protective process.