Activation of negative regulators of the hypoxia-inducible factor (HIF) pathway in human end-stage heart failure

Zolk, Oliver; Solbach, Thomas F.; Eschenhagen, Thomas; Weidemann, Alexander; Fromm, Martin F.

doi:10.1016/j.bbrc.2008.08.152

Cited by 50 publications

(33 citation statements)

References 33 publications

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“…Zolk et al (67) demonstrated that the mRNA expression level of HIF-1α is 51% lower in cardiac tissue from a patient with heart failure compared with that of a healthy control. By contrast, the expression of HIF-2α remains unchanged and the mRNA expression of HIF-3α is 72% higher in cardiac tissue from a patient with heart failure compared with healthy control (67).…”

Section: Association Between Hif-3 and Diseasesmentioning

confidence: 82%

Progress on hypoxia-inducible factor-3: Its structure, gene regulation and biological function (Review)

Yang

Xiong

et al. 2015

Molecular Medicine Reports

106

103

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Abstract. Hypoxia inducible factors (HIFs) are transcription factors, which are commonly expressed in mammals, including humans. The HIFs consist of hypoxia-regulated α and oxygen-insensitive β subunits, and are key regulators of gene expression during hypoxia in normal and solid tumor tissues. Three members of the HIF family, HIF-1α, HIF-2α, and HIF-3α, are currently known. HIF-3α differs from HIF-1α and HIF-2α in protein structure and regulation of gene expression. For a long time, HIF-3α was considered as a negative mediator of HIF-regulated genes. HIF-3 has a transcriptional regulatory function, which negatively affects gene expression by competing with HIF-1α and HIF-2α in binding to transcriptional elements in target genes during hypoxia. Previously, certain target genes of HIF-3α have been identified, confirming the role of HIF-3α as a transcription factor. In this review, the protein structure, gene regulation and biological function of HIF-3 are discussed based on the literature.

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Section: Association Between Hif-3 and Diseasesmentioning

confidence: 82%

Progress on hypoxia-inducible factor-3: Its structure, gene regulation and biological function (Review)

Yang

Xiong

et al. 2015

Molecular Medicine Reports

106

103

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“…aHIF, a natural antisense transcript of HIF1α, is overexpressed in the failing heart. 22 By modulating the stability of HIF1α messenger RNA, aHIF has the capacity to regulate angiogenesis, an important component of the response of the heart to ischemia. ANRIL is the best replicated genetic risk factor for coronary artery disease 23 and regulates genes involved in glucose and fatty acid metabolism.…”

Section: Discussionmentioning

confidence: 99%

Long Noncoding RNAs in Patients With Acute Myocardial Infarction

Vausort

Wagner²,

Devaux

2014

Circulation Research

447

352

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Rationale: Long noncoding RNAs (lncRNAs) constitute a novel class of noncoding RNAs that regulate gene expression. Although recent data suggest that lncRNAs may be associated with cardiac disease, little is known about lncRNAs in the setting of myocardial ischemia. Objective: To measure lncRNAs in patients with myocardial infarction (MI). Methods and Results: We enrolled 414 patients with acute MI treated by primary percutaneous coronary intervention. Blood samples were harvested at the time of reperfusion. Expression levels of 5 lncRNAs were measured in peripheral blood cells by quantitative polymerase chain reaction: hypoxia inducible factor 1A antisense RNA 2, cyclin-dependent kinase inhibitor 2B antisense RNA 1 (ANRIL), potassium voltage-gated channel, KQT-like subfamily, member 1 opposite strand/antisense transcript 1 (KCNQ1OT1), myocardial infarction–associated transcript, and metastasis-associated lung adenocarcinoma transcript 1. Levels of hypoxia inducible factor 1A antisense RNA 2, KCNQ1OT1, and metastasis-associated lung adenocarcinoma transcript 1 were higher in patients with MI than in healthy volunteers ( P <0.01), and levels of ANRIL were lower in patients with MI ( P =0.003). Patients with ST-segment–elevation MI had lower levels of ANRIL ( P <0.001), KCNQ1OT1 ( P <0.001), myocardial infarction–associated transcript ( P <0.001), and metastasis-associated lung adenocarcinoma transcript 1 ( P =0.005) when compared with patients with non–ST-segment–elevation MI. Levels of ANRIL were associated with age, diabetes mellitus, and hypertension. Patients presenting within 3 hours of chest pain onset had elevated levels of hypoxia inducible factor 1A antisense RNA 2 when compared with patients presenting later on. ANRIL, KCNQ1OT1, myocardial infarction–associated transcript, and metastasis-associated lung adenocarcinoma transcript 1 were significant univariable predictors of left ventricular dysfunction as assessed by an ejection fraction ≤40% at 4-month follow-up. In multivariable and reclassification analyses, ANRIL and KCNQ1OT1 improved the prediction of left ventricular dysfunction by a model, including demographic features, clinical parameters, and cardiac biomarkers. Conclusions: Levels of lncRNAs in blood cells are regulated after MI and may help in prediction of outcome. This motivates further investigation of the role of lncRNAs after MI.

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“…Chu et al (41) recently also reported that overexpression of Hif-1␣ directly triggered neonatal cardiomyocyte hypertrophy. More importantly, Zolk et al (42) observed that the levels of Hif-1␣ were significantly decreased, whereas PHD3 (Egln3) was up-regulated in human end-stage failing hearts. Hence, these data together with our findings suggest that miR-223 may be utilized as a potential agent to elevate Hif-1␣ levels and, consequently, rescue heart failure.…”

Section: Volume 291 • Number 30 • July 22 2016mentioning

confidence: 99%

Overexpression of miR-223 Tips the Balance of Pro- and Anti-hypertrophic Signaling Cascades toward Physiologic Cardiac Hypertrophy

Yang

Wang

et al. 2016

Journal of Biological Chemistry

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MicroRNAs (miRNAs) have been extensively examined in pathological cardiac hypertrophy. However, few studies focused on profiling the miRNA alterations in physiological hypertrophic hearts. In this study we generated a transgenic mouse model with cardiac-specific overexpression of miR-223. Our results showed that elevation of miR-223 caused physiological cardiac hypertrophy with enhanced cardiac function but no fibrosis. Using the next generation RNA sequencing, we observed that most of dys-regulated genes (e.g. Atf3/5, Egr1/3, Sfrp2, Itgb1, Ndrg4, Akip1, Postn, Rxfp1, and Egln3) in miR-223-transgenic hearts were associated with cell growth, but they were not directly targeted by miR-223. Interestingly, these dysregulated genes are known to regulate the Akt signaling pathway. We further identified that miR-223 directly interacted with 3-UTRs of FBXW7 and Acvr2a, two negative regulators of the Akt signaling. However, we also validated that miR-223 directly inhibited the expression of IGF-1R and ␤1-integrin, two positive regulators of the Akt signaling. Lastly, Western blotting did reveal that Akt was activated in miR-223-overexpressing hearts. Adenovirus-mediated overexpression of miR-223 in neonatal rat cardiomyocytes induced cell hypertrophy, which was blocked by the addition of MK2206, a specific inhibitor of Akt. Taken together, these data represent the first piece of work showing that miR-223 tips the balance of promotion and inactivation of Akt signaling cascades toward activation of Akt, a key regulator of physiological cardiac hypertrophy. Thus, our study suggests that the ultimate phenotype outcome of a miRNA may be decided by the secondary net effects of the whole target network rather than by several primary direct targets in an organ/tissue.Cardiac hypertrophy is an adaptive mechanism of cardiomyocytes to different forms of injury or stress, such as myocardial infarction, hypertension, and valve disease (pathological) or chronic exercise training (physiological) (1). Both pathological and physiological cardiac hypertrophy types are featured with increased myocyte size, but they have distinct molecular and functional phenotypes (2). Pathological cardiac hypertrophy is often associated with interstitial fibrosis and increased myocyte necrosis/apoptosis, leading to cardiac dysfunction (1, 2). By contrast, exercise training-induced physiological cardiac hypertrophy is characterized by overall normal cardiac structure and function, presenting an adaptive beneficial response (1, 2). Indeed, exercise training is clinically recommended as the most effective non-pharmacological intervention to reduce cardiovascular disease (2). Thus, elucidating the molecular mechanisms underlying physiological cardiac hypertrophy would help us identify novel therapies for the treatment of cardiovascular disease.MicroRNAs (miRNAs) 3 are small, endogenous, non-coding RNAs of ϳ22 to 26 nucleotides in length that function primarily as post-transcriptional regulators (3). Importantly, a single miRNA does not only regulate one gene ...

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Activation of negative regulators of the hypoxia-inducible factor (HIF) pathway in human end-stage heart failure

Cited by 50 publications

References 33 publications

Progress on hypoxia-inducible factor-3: Its structure, gene regulation and biological function (Review)

Progress on hypoxia-inducible factor-3: Its structure, gene regulation and biological function (Review)

Long Noncoding RNAs in Patients With Acute Myocardial Infarction

Overexpression of miR-223 Tips the Balance of Pro- and Anti-hypertrophic Signaling Cascades toward Physiologic Cardiac Hypertrophy

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