Functional Network Analysis Reveals Versatile MicroRNAs in Human Heart

Xu, Yingqi; Zhu, Wenliang; Sun, Yong; Wang, Zhe; Yuan, Wei; Du, Zhenhong

doi:10.1159/000430324

Cited by 16 publications

(10 citation statements)

References 61 publications

(68 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Growing evidence indicates that miRNAs are critical regulators of cardiovascular development and physiology, and are thus directly involved in the pathophysiology of many cardiovascular diseases [31]. MicroRNAs are reported to be involved in cardiac reactions to myocardial infarction and heart failure [32]. They are powerful modifiers of cardiac aging, which is one of the most hazardous risks for cardiovascular diseases [33].…”

Section: Discussionmentioning

confidence: 99%

δ-Opioid Receptor Activation and MicroRNA Expression in the Rat Heart Under Prolonged Hypoxia

Zhi

Li²,

Shao³

et al. 2016

Cell Physiol Biochem

View full text Add to dashboard Cite

Background: Hypoxic/ischemic injury to the heart is a frequently encountered clinical problem with limited therapeutic options. Since microRNAs (miRNAs) are involved in hypoxic/ischemic events, and δ-opioid receptor (DOR) activation is known to protect against hypoxic/ischemic injury, we speculated on the involvement of DOR activation in altering miRNA expression in the heart under hypoxic conditions. The present study aimed to test our hypothesis. Methods: Male Sprague Dawley rats were exposed to hypoxia (9.5-10% O₂) for 1, 5, or 10 days with or without DOR activation. The target miRNAs were selected from TaqMan low-density array (TLDA) data and were further analyzed by quantitative real-time PCR. Results: We found that: 1) hypoxia alters the miRNA expression profiles depending on the hypoxic duration; 2) DOR activation shifts miRNA expression profiles in normoxic conditions and upregulates miR-128a-3p, miR-134-5p, miR-135a, miR-193a-3p, miR-196a, miR-324-3p, and miR-338; and 3) DOR activation modifies hypoxia-induced changes in miRNA expression and increases the levels of miR-128a-3p, miR-134-5p, miR-135a, miR-193a-3p, miR-196a, miR-324-3p, miR-141, miR-200b, and miR-324-3p. For example, miR-196c-5p decreased by 50% while miR-135a-5p increased 2.9 fold after 10 days under hypoxic conditions. Moreover, DOR activation further strengthened the hypoxia-induced increase of the levels of miR-7a-5p. When DOR was activated using UFP-512, the level of miR-107-3p significantly increased 1 day after the administration of UFP-512, but gradually decreased back to normal under normoxia. Conclusion: Hypoxia significantly modifies the miRNA profile in the heart, which can be mimicked or modified by DOR activation. Defining the targeted pathways that regulate the diverse cellular and molecular functions of miRNAs may provide new insights into potential therapies for hypoxic/ischemic injury of the heart.

show abstract

Section: Discussionmentioning

confidence: 99%

δ-Opioid Receptor Activation and MicroRNA Expression in the Rat Heart Under Prolonged Hypoxia

Zhi

Li²,

Shao³

et al. 2016

Cell Physiol Biochem

View full text Add to dashboard Cite

show abstract

“…Several miRNAs have been reported to play prominent regulatory roles in cardiac excitability and heart pathological processes, including AMI, cardiac hypertrophy, and diabetic cardiomyopathy, through targeting the relevant ion channels encoding genes [21][22][23][24][25][26][27]. For instance, cardiac enriched microRNA-1 (miR-1) participates in regulating pathophysiological processes of coronary artery disease, cardiac hypertrophy [28] and ischemic arrhythmia [21,29]. The proarrhythmic property of miR-1 has been verified not only in ischemic hearts but also in normal hearts [21].…”

Section: Introductionmentioning

confidence: 99%

MiR-223-3p as a Novel MicroRNA Regulator of Expression of Voltage-Gated K+ Channel Kv4.2 in Acute Myocardial Infarction

Xue

Zhang

et al. 2016

Cell Physiol Biochem

View full text Add to dashboard Cite

Background/Aims: Acute myocardial infarction (AMI) is a devastating cardiovascular disease with a high rate of morbidity and mortality, partly due to enhanced arrhythmogenicity. MicroRNAs (miRNAs) have been shown to participate in the regulation of cardiac ion channels and the associated arrhythmias. The purpose of this study was to test our hypothesis that miR-223-3p contributes to the electrical disorders in AMI via modulating KCND2, the gene encoding voltage-gated channel Kv4.2 that carries transient outward K⁺ current I_to. Methods: AMI model was established in male Sprague-Dawley (SD) rats by left anterior descending artery (LAD) ligation. Evans blue and TTC staining was used to measure infarct area. I_to was recorded in isolated ventricular cardiomyocytes or cultured neonatal rat ventricular cells (NRVCs) by whole-cell patch-clamp techniques. Western blot analysis was employed to detect the protein level of Kv4.2 and real-time RT-PCR to determine the transcript level of miR-223-3p. Luciferase assay was used to examine the interaction between miR-223-3p and KCND2 in cultured NRVCs. Results: Expression of miR-223-3p was remarkably upregulated in AMI relative to sham control rats. On the contrary, the protein level of Kv4.2 and I_to density were significantly decreased in AMI. Consistently, transfection of miR-223-3p mimic markedly reduced Kv4.2 protein level and Ito current in cultured NRVCs. Co-transfection of AMO-223-3p (an antisense inhibitor of miR-223-3p) reversed the repressive effect of miR-223-3p. Luciferase assay showed that miR-223-3p, but not the negative control, substantially suppressed the luciferase activity, confirming the direct binding of miR-223-3p to the seed site within the KCND2 sequence. Finally, direct intramuscular injection of AMO-223-3p into the ischemic myocardium to knockdown endogenous miR-223-3p decreased the propensity of ischemic arrhythmias. Conclusions: Upregulation of miR-223-3p in AMI repressed the expression of KCND2/Kv4.2 resulting in reduction of I_to density that can cause APD prolongation and promote arrhythmias in AMI, and therefore knockdown of endogenous miR-223-3p might be considered a new approach for antiarrhythmic therapy of ischemic arrhythmias.

show abstract

“…Among these, we selected several of the most affected miRNAs (miR-7-1-3p, miR-32-3p, miR-211-5p, and miR-548u-3p) for evaluation by qRT-PCR (normalized to miR-16) in the validation cohort. Notably, miR-7-1-3p and miR-211-5p are reported biomarkers of ischemic heart disease (11)(12)(13). The concentrations of these miRNAs were significantly different in all patients with sarcoidosis, taken collectively, relative to control subjects.…”

Section: To the Editormentioning

confidence: 97%