Aberrant Cardiac Long Noncoding RNA Expression Following Alterations in Thyroid Hormones
Authors: Rajagopalan Viswanathan , Tahseen Sabrina 
Published: April 2020

Background

Heart failure (HF) mortality is on the rise and altered thyroid hormone (TH) function is a major risk factor. HF can be a result of either decreased (hypothyroidism; HypoTH) or increased (hyperthyroidism; HyperTH) serum TH levels. THs regulate cardiac physiology including contractility and relaxation. We recently showed safe, cardioprotective effects with oral treatment of active form of THs in several rodent models of cardiovascular disorders. Moving forward, novel heart‐specific targets in TH pathway are warranted. About 98% of the genome is non‐protein‐coding and over 90% is transcribable. Long noncoding RNA (lncRNA; transcripts >200 nucleotides) genes outnumber protein‐coding genes by several fold. Deiodinase‐3 converts active forms of THs into inactive metabolites, and its chromosomal domain also encode maternally expressed lncRNAs. However, role of lncRNAs in TH‐mediated cardiac effects is unknown. We hypothesize that alterations in TH levels will impair cardiac lncRNA expression.

Methods

HypoTH was induced by feeding adult C57BL/6 mice with 0.15% propylthiouracil with 0.1% methimazole for 5 weeks. HyperTH was established by injecting TH (T4; 1 μg/g i.p.) every 48 hours. Females were used because they maintain a more stable body mass over time than males. Furthermore, women have higher incidence of thyroid anomalies. Echocardiography and heart gravimetry were performed and results analyzed by analysis of variance with Tukey's multiple comparisons test (n=3–5/group). We also performed quantitative real‐time PCR using lncRNA‐specific array of 86 different targets following pre‐amplification. Array reproducibility, reverse transcription efficiency, absence of genomic DNA contamination and normalization were ensured.

Results

Serum total T4 levels were decreased in HypoTH (p<0.05) and increased in HyperTH (p<0.01) [Control: 2.17±0.4; HypoTH: 0.8±0.2; HyperTH: 12.8±2.4; ug/dl]. While HypoTH hearts were atrophic (p<0.05), HyperTH hearts showed significant hypertrophy (p<0.0001). Heart weight to body weight ratio was 4.38±0.2 in controls, 3.8±0.1 in HypoTH and 5.9±0.1 in HyperTH. Left and right ventricular ratios also followed similar patterns (p<0.05). Following HypoTH, echocardiographic left ventricular end‐systolic dimension significantly increased (p<0.05) while fractional shortening decreased (p<0.01). Heart rate decreased with HypoTH and increased with HyperTH (p<0.01). We began investigating involvement of lncRNAs related to inflammatory and immune mechanisms that can be relevant in both TH abnormalities and HF. Quantitative real‐time PCR showed that several of these cardiac lncRNAs were differentially expressed following alterations in TH levels (p<0.05). Importantly, two lncRNAs were significantly downregulated (2.9‐ and 1.73‐fold) in HypoTH, but upregulated (3.4‐ and 1.67‐fold) in HyperTH ventricles. Another lncRNA was significantly increased in HypoTH (2.1‐fold), but decreased with HyperTH (7.63‐fold).

Conclusions

This is the first report to present aberrations in cardiac lncRNAs following altered TH levels. Taken together, this demonstrates potential TH‐dependent regulation of lncRNAs in mammalian hearts that may offer clinical significance.

Support or Funding Information

NYITCOM