Approaching Sex Differences in Cardiovascular Non-Coding RNA Research

Abstract

Cardiovascular disease (CVD) is the biggest cause of sickness and mortality worldwide in both males and females. Clinical statistics demonstrate clear sex differences in risk, prevalence, mortality rates, and response to treatment for different entities of CVD. The reason for this remains poorly understood. Non-coding RNAs (ncRNAs) are emerging as key mediators and biomarkers of CVD. Similarly, current knowledge on differential regulation, expression, and pathology-associated function of ncRNAs between sexes is minimal. Here, we provide a state-of-the-art overview of what is known on sex differences in ncRNA research in CVD as well as discussing the contributing biological factors to this sex dimorphism including genetic and epigenetic factors and sex hormone regulation of transcription. We then focus on the experimental models of CVD and their use in translational ncRNA research in the cardiovascular field. In particular, we want to highlight the importance of considering sex of the cellular and pre-clinical models in clinical studies in ncRNA research and to carefully consider the appropriate experimental models most applicable to human patient populations. Moreover, we aim to identify sex-specific targets for treatment and diagnosis for the biggest socioeconomic health problem globally.

RNA-seq Characterization of Sex-Differences in Adipose Tissue of Obesity Affected Patients: Computational Analysis of Differentially Expressed Coding and Non-Coding RNAs

“…Indeed, the most notable contribution of lncRNA to sex differences is provided by the lncRNA XIST, encoded on the chromosome X [ 32 , 33 , 34 ]. Sexual dysmorphisms correlated with lncRNAs have been found for the brain, in male sex determination, and even cardiovascular diseases, but no specific evidence has to this day been reported for the adipose tissue and obesity [ 35 , 36 , 37 ]. To this end, this research work is aimed at the characterization the transcriptional differences present in the SAT of men and women, with an additional focus on the role of lncRNAs.…”

Recent Update on the Molecular Mechanisms of Gonadal Steroids Action in Adipose Tissue

“…A global regulator of gene expression are microRNAs. Although sex-related differences in the expression profile of microRNAs are still poorly understood [ 282 ], there is evidence that both sex chromosomes and sex hormones can cause differences in microRNAs expression [ 33 ]. At the same time, microRNAs can be a link between coexisting metabolic diseases, as each microRNA can interact with dozens of targets.…”

“…Knowledge on the role of miRNAs in the regulation of metabolism and development of metabolic diseases is developing intensively [ 276 ]. The role of miRNAs in the development of metabolic diseases such as obesity, T2D, polycystic ovary syndrome, nonalcoholic fatty disease, cardiovascular and inflammatory diseases was recently reviewed [ 277 , 278 , 279 , 280 , 281 , 282 , 283 ]. Moreover, the expression of aquaporin isoforms associated with metabolic diseases is also regulated by microRNAs [ 284 ].…”

Genetic, Molecular, and Cellular Determinants of Sex-Specific Cardiovascular Traits

“…Noncoding RNA genes, compared with protein-coding RNA genes, produce nontranslated but functional RNA molecules that regulate translation and degradation of mRNA. 186 Noncoding RNA can be further categorized in microRNA (<200 nucleotides), long noncoding RNA (>200 nucleotides), and circular RNA. 186 The more recently discovered long noncoding RNAs can function in the epigenetic imprinting process.…”