Regulatory Roles of Long Noncoding RNAs in Arterial Stiffness and Hypertension.

Background: Arterial stiffness, commonly assessed via pulse wave velocity (PWV), is marked by reduced arterial elasticity and serves as a significant risk factor for cardiovascular disease and an early indicator of hypertension. This study investigated the regulatory roles of long noncoding RNAs (lncRNAs) in modulating mRNAs associated with arterial stiffness and hypertension, with a particular focus on Black individuals, a population disproportionately impacted by hypertension.

Methods: We utilized whole-blood transcriptome sequencing data from 2 Black cohorts with high hypertension prevalence: the GENE-FORECAST (the Genomics, Environmental Factors, and Social Determinants of Cardiovascular Disease in African Americans Study; 436 subjects) and the MH-GRID study (Minority Health Genomics and Translational Research Bio-Repository Database; 179 subjects). Our objectives were to: (1) identify lncRNAs and mRNAs differentially expressed between the upper and lower tertiles of PWV; (2) determine differentially expressed lncRNAs associated with the expression levels of each differentially expressed mRNA; and (3) link the lncRNA-modulated mRNAs to hypertension across both data sets. For each of the 3 analyses, results were considered significant if the false discovery rate-adjusted P value was ≤0.05 in the discovery data set, the P value was ≤0.05 in the validation data set, and the effect size was consistent in direction across the 2 data sets.

Results: Differential expression analysis revealed, respectively 1035 mRNAs and 31 lncRNAs differentially expressed between upper and lower PWV groups. Then, lncRNA-mRNA pairs significantly associated were identified, involving 31 unique lncRNAs and 1034 unique mRNAs. Finally, 22 of the lncRNA-modulated mRNAs initially linked to PWV were found to be associated with hypertension and replicated. Interestingly, 30 lncRNAs were linked to the expression of UCP2 (Uncoupling Protein 2), a gene implicated in oxidative stress and endothelial function.

Conclusions: Our findings underscore the significant roles of lncRNAs in regulating gene expression associated with arterial stiffness and hypertension. The differential expression of UCP2 in relation to PWV and hypertension, along with its potential regulation by lncRNAs, offers valuable insights into the molecular mechanisms underlying arterial stiffness and its connection with hypertension.