MicroRNA profiles in plasma samples from young metabolically healthy obese patients and miRNA‐21 are associated with diastolic dysfunction via TGF‐β1/Smad pathway

Abstract

Background: Metabolically healthy obese patients accounts for a large part of obese population, but its clinical significance and cardiac dysfunction are often underestimated. The microRNA profiles of metabolically healthy obese patients were investigated in the study, and the selected microRNA (miRNA) based on our microarray assay will be further verified in a relatively large metabolically healthy obese population.Methods: microRNA microarray was performed from six metabolically healthy obese and 6 health control blood samples. Based on the bioinformatics analysis, we further measured RT-PCR, fibrosis markers, echocardiograms, and TGF-β1/Smad signaling pathway in 600 metabolically healthy obese population. Results:We found that miRNAs expression characteristics in metabolically healthy obese groups were markedly different from healthy control group. MiRNA-21 was significantly increased in the samples of metabolically healthy obese patients.Besides, miRNA-21 levels were associated with cardiac fibrosis marker. Meanwhile, higher miRNA-21 levels were related to elevated E/E′. Besides, patients with the highest miRNA-21 quartile showed the lowest ratio of E/A. These associations between miRNA-21 and diastolic function parameters were independent of obesity and other confounding variables. Of note, TGF-β1and Smad 3 were significantly upregulated while Smad 7 was downregulated according to the miRNA-21 quartiles in metabolically healthy obese group. Conclusions:We demonstrated the profiles of circulating microRNAs in metabolically healthy obese patients. Increased plasma miRNA-21 levels were related to impaired diastolic function independent of other relevant confounding variables.MiRNA-21 could be one of the mechanistic links between obesity and diastolic dysfunction through regulating cardiac fibrosis via TGF-β1/Smad signaling pathway in obese hearts, which may serve as a novel target of disease intervention.

Toward Regulatory Effects of Curcumin on Transforming Growth Factor-Beta Across Different Diseases: A Review

“…It is worth mentioning that microRNAs (miRs) can function as upstream regulators of TGF-β. In stimulation of cardiac fibrosis, miR-21 activates TGF-β/Smad3 axis, while it decreases expression of Smad7, as an I-Smad ( Yang et al, 2020 ).…”

Adipose‐derived miRNAs as potential biomarkers for predicting adulthood obesity and its complications: A systematic review and bioinformatic analysis

“…All, except five, studies used a case-control design, including five cohort studies. Studies on patients with obesity were conducted in Spain [19][20][21][22][23] , Korea [24][25][26][27] , Singapore 28 , China [29][30][31][32][33] , the United States [34][35][36] , Algeria 37 , The Netherlands 38,39 , U.A.R. (Egypt) 40,41 , Iran 42 , Ireland 43 , Turkey 44 , Italy 45 , Kuwait 46 , and New Zealand 47 .…”

“…These studies focused primarily on adipose secretion miRNAs 16,19,21–23,27,29,30,32,36,38,39,43,53,57,60–71 . Seventeen studies did not specify the selection criteria for patients with obesity but met all other criteria prescribed by the World Health Organization, including BMI ≥ 30 kg/m 2 21,24,28,31,32,34,36,37,39,41,45,46,70–72 . None of the studies indicated whether any other variables were controlled for miRNA expression.…”

Non-coding RNAs in the pathophysiology of heart failure with preserved ejection fraction

“…Elevated levels of circulating miR-21 were also observed in obese patients, which exhibited a correlation with diastolic dysfunction and concomitant with increased plasma levels of TGF-β and Smad3 and decreased Smad7. miR-21 upregulation was also linked to increased fibrosis markers, including elevated mRNA plasma levels of α-SMA, Collagen-I and Collagen-III ( 123 ). Interestingly, cardiac miR-21 levels were shown to be downregulated in type-2 DM db/db mouse model, leading to diastolic dysfunction with preserved ejection fraction ( 124 ).…”