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. 2021 May 21:12:674252.
doi: 10.3389/fphar.2021.674252. eCollection 2021.

MicroRNA-33b is a Potential Non-Invasive Biomarker for Response to Atorvastatin Treatment in Chilean Subjects With Hypercholesterolemia: A Pilot Study

Carmen Gloria Ubilla  1 , Yalena Prado  1 , Jeremy Angulo  1 , Ignacio Obreque  1 , Isis Paez  1 , Nicolás Saavedra  1 , Kathleen Saavedra  1 , Tomás Zambrano  2 , Luis A Salazar  1
Affiliations

MicroRNA-33b is a Potential Non-Invasive Biomarker for Response to Atorvastatin Treatment in Chilean Subjects With Hypercholesterolemia: A Pilot Study

Carmen Gloria Ubilla et al. Front Pharmacol. .

Abstract

Evidence accumulated so far indicates that circulating levels of microRNAs (miRNAs) are associated with several pathologies. Therefore, differential expression of extracellular miRNAs exhibits promising potential for screening and diagnosis purposes. We evaluated plasma miRNAs in response to the lipid-lowering drug atorvastatin in patients with hypercholesterolemia (HC) and controls.

Methods: We selected miRNAs based on previous data reported by our group and also by employing bioinformatics tools to identify 10 miRNAs related to cholesterol metabolism and statin response genes. Following miRNA identification, we determined plasma levels of miRNA-17-5p, miRNA-30c-5p, miRNA-24-3p, miRNA-33a-5p, miRNA-33b-5p, miRNA-29a-3p, miRNA-29b-3p, miRNA-454-3p, miRNA-590-3p and miRNA-27a-3p in 20 HC patients before and after 1 month of 20 mg/day atorvastatin treatment, evaluating the same miRNA set in a group of 20 healthy subjects, and employing qRT-PCR to determine differential miRNAs expression.

Results: HC individuals showed significant overexpression of miRNA-30c-5p and miRNA-29b-3p vs. NL (p = 0.0008 and p = 0.0001, respectively). Once cholesterol-lowering treatment was concluded, HC individuals showed a substantial increase of three extracellular miRNAs (miRNA-24-3p, miRNA-590, and miRNA-33b-5p), the latter elevated more than 37-fold (p = 0.0082).

Conclusion: Data suggest that circulating miRNA-30c-5p and miRNA-29b-3p are associated with hypercholesterolemia. Also, atorvastatin induces a strong elevation of miRNA-33b-5p levels in HC individuals, which could indicate an important function that this miRNA may exert upon atorvastatin therapy. Additional studies are needed to clarify the role of this particular miRNA in statin treatment.

Keywords: atorvastatin; circulating microRNAs; epidrugs; hypercholesterolemia; statins.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Expression of circulating miRNA-30c and miRNA-29b in hypercholesterolemic patients vs. controls. *Mann-Whitney test. C. elegans miRNA-39 was used as a normalizing control. The values of the threshold cycle (Ct) of each miRNA, normalized against this sequence (ΔCt = Ct target miRNA—Ct endogenous control), the plasma expression levels of these miRNAs were calculated according to 2−ΔCt method. The total number of samples analyzed was 20 for each study group.
FIGURE 2
FIGURE 2
Network of validated gene targets for miRNA-33b-5p. ABCA1: ATP binding cassette subfamily A member one; BCL2: B-cell lymphoma two Apoptosis Regulator; CREB1: cAMP responsive element binding protein one; G6PC: glucose-6-phosphatase, catalytic; HMGA2: High Mobility Group AT-Hook two; MYC: MYC Proto-Oncogene, BHLH Transcription Factor; PCK1: Phosphoenolpyruvate carboxykinase one; PIM1: Proto-Oncogene, Serine/Threonine Kinase; RORA: RAR Related Orphan Receptor A; SRC: SRC Proto-Oncogene, Non-Receptor Tyrosine Kinase; TWIST1: Twist Family BHLH Transcription Factor 1; XIAP: X-linked inhibitor of apoptosis; ZEB1: zinc finger E-box binding homeobox 1.
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