Molecular mechanism of diabetic cardiomyopathy and modulation of microRNA function by synthetic oligonucleotides

Ghosh, Nilanjan; Katare, Rajesh

doi:10.1186/s12933-018-0684-1

Cited by 56 publications

(38 citation statements)

References 281 publications

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“…Diabetic cardiomyopathy (DCM) is characterized by early diastolic abnormalities and clinical heart failure without dyslipidemia, hypertension, or coronary artery disease 6 . The pathological cardiac remodeling process that drives DCM is complex, which includes systemic metabolic disorders, inflammation, oxidative stress, and apoptosis 7 . These pathologic changes conjointly enhance cardiac tissue interstitial fibrosis, cardiac diastolic dysfunction, and then systolic dysfunction and ultimately clinical HF 6 .…”

Section: Introductionmentioning

confidence: 99%

High-mobility group AT-hook 1 promotes cardiac dysfunction in diabetic cardiomyopathy via autophagy inhibition

Liu

Cai

et al. 2020

Cell Death Dis

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High-mobility group AT-hook1 (HMGA1, formerly HMG-I/Y), an architectural transcription factor, participates in a number of biological processes. However, its effect on cardiac remodeling (refer to cardiac inflammation, apoptosis and dysfunction) in diabetic cardiomyopathy remains largely indistinct. In this study, we found that HMGA1 was upregulated in diabetic mouse hearts and high-glucose-stimulated cardiomyocytes. Overexpression of HMGA1 accelerated high-glucose-induced cardiomyocyte inflammation and apoptosis, while HMGA1 knockdown relieved inflammation and apoptosis in cardiomyocytes in response to high glucose. Overexpression of HMGA1 in mice heart by adeno-associated virus 9 (AAV9) delivery system deteriorated the inflammatory response, increased apoptosis and accelerated cardiac dysfunction in streptozotocin-induced diabetic mouse model. Knockdown of HMGA1 by AAV9-shHMGA1 in vivo ameliorated cardiac remodeling in diabetic mice. Mechanistically, we found that HMGA1 inhibited the formation rather than the degradation of autophagy by regulating P27/CDK2/mTOR signaling. CDK2 knockdown or P27 overexpression blurred HMGA1 overexpression-induced deteriorating effects in vitro. P27 overexpression in mice heart counteracted HMGA1 overexpression-induced increased cardiac remodeling in diabetic mice. The luciferase reporter experiment confirmed that the regulatory effect of HMGA1 on P27 was mediated by miR-222. In addition, a miR-222 antagomir counteracted HMGA1 overexpression-induced deteriorating effects in vitro. Taken together, our data indicate that HMGA1 aggravates diabetic cardiomyopathy by directly regulating miR-222 promoter activity, which inhibits P27/mTOR-induced autophagy.

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Section: Introductionmentioning

confidence: 99%

High-mobility group AT-hook 1 promotes cardiac dysfunction in diabetic cardiomyopathy via autophagy inhibition

Liu

Cai

et al. 2020

Cell Death Dis

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“…Recently, a critical role of microRNA (miR)s in the pathogenesis of cardiovascular diseases (CVD) and diabetes-related complications has been demonstrated [17][18][19]. Binding of specific target transcripts by miRs leads to mRNA degradation and translational repression.…”

Section: Introductionmentioning

confidence: 99%

Vascular miR-181b controls tissue factor-dependent thrombogenicity and inflammation in type 2 diabetes

Witkowski

Saffarzadeh

et al. 2020

Cardiovasc Diabetol

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Background: Diabetes mellitus is characterized by chronic vascular inflammation leading to pathological expression of the thrombogenic full length (fl) tissue factor (TF) and its isoform alternatively-spliced (as) TF. Blood-borne TF promotes factor (F) Xa generation resulting in a pro-thrombotic state and cardiovascular complications. MicroRNA (miR)s impact gene expression on the post-transcriptional level and contribute to vascular homeostasis. Their distinct role in the control of the diabetes-related procoagulant state remains poorly understood. Methods: In a cohort of patients with poorly controlled type 2 diabetes (n = 46) plasma levels of miR-181b were correlated with TF pathway activity and markers for vascular inflammation. In vitro, human microvascular endothelial cells (HMEC)-1 and human monocytes (THP-1) were transfected with miR-181b or anti-miR-181b and exposed to tumor necrosis factor (TNF) α or lipopolysaccharides (LPS). Expression of TF isoforms, vascular adhesion molecule (VCAM) 1 and nuclear factor (NF) κB nuclear translocation was assessed. Moreover, aortas, spleen, plasma, and bone marrowderived macrophage (BMDM)s of mice carrying a deletion of the first miR-181b locus were analyzed with respect to TF expression and activity. Results: In patients with type 2 diabetes, plasma miR-181b negatively correlated with the procoagulant state as evidenced by TF protein, TF activity, d-dimer levels as well as markers for vascular inflammation. In HMEC-1, miR-181b abrogated TNFα-induced expression of flTF, asTF, and VCAM1. These results were validated using the anti-miR-181b. Mechanistically, we confirmed a miR-181b-mediated inhibition of importin-α3 (KPNA4) leading to reduced nuclear translocation of the TF transcription factor NFκB. In THP-1, miR-181b reduced both TF isoforms and FXa generation in response to LPS due to targeting phosphatase and tensin homolog (PTEN), a principal inducer for TF in monocytes. Moreover, in miR-181−/− animals, we found that reduced levels of miR-181b were accompanied by increased TF, VCAM1, and KPNA4 expression in aortic tissue as well as increased TF and PTEN expression in spleen. Finally, BMDMs of miR-181−/− mice showed increased TF expression and FXa generation upon stimulation with LPS. Conclusions: miR-181b epigenetically controls the procoagulant state in diabetes. Reduced miR-181b levels contribute to increased thrombogenicity and may help to identify individuals at particular risk for thrombosis.

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“…In the present study, downregulation of miR-20b inhibited H22 cell growth. It is well known that miRNAs participate in oncogenesis by regulating the expression of their target genes (17). miR-20b is a member of the miR-106a-363 and miR-7 gene families (9), which are active in various types of human tumor (10).…”

Section: Discussionmentioning

confidence: 99%

MicroRNA‑20b promotes proliferation of H22 hepatocellular carcinoma cells by targeting PTEN

Luo

et al. 2019

Oncol Lett

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MicroRNAs (miRNAs/miRs) are small, noncoding RNA molecules that are closely associated with the occurrence and development of tumors. miR-20b is overexpressed in hepatocellular carcinoma cell lines and tissues. However, it is not clear whether miR-20b can promote the proliferation of hepatocellular carcinoma cells. In the present study, the proliferation of H22 mouse hepatocellular carcinoma cells was detected using the Cell Counting Kit-8 assay. MiRanda software was used to predict the binding sites of miR-20b to the 3'-untranslated region (3'-UTR) of phosphatase and tensin homolog (PTEN). The 3'-UTR sequence of the PTEN gene was amplified using the polymerase chain reaction in H22 cells. The recombinant plasmid or empty plasmid was co-transfected with miR-20b mimics or miR-20b scramble into HeLa cells, and luciferase activity was assessed by Dual-Luciferase ® Reporter Assay System 24 h post-transfection. In the present study, miR-20b knockdown significantly inhibited the proliferation of H22 mouse hepatocellular carcinoma cells. In addition, miR-20b inhibition upregulated the expression of PTEN, and it was revealed that miR-20b may directly target the 3'-untranslated region of the PTEN gene. Downregulation of PTEN partially reversed the anti-proliferative effect of miR-20b on H22 cells. In conclusion, miR-20b may promote H22 cell proliferation by targeting PTEN, providing a rationale for further study investigating novel therapeutic strategies for liver cancer.

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Molecular mechanism of diabetic cardiomyopathy and modulation of microRNA function by synthetic oligonucleotides

Cited by 56 publications

References 281 publications

High-mobility group AT-hook 1 promotes cardiac dysfunction in diabetic cardiomyopathy via autophagy inhibition

High-mobility group AT-hook 1 promotes cardiac dysfunction in diabetic cardiomyopathy via autophagy inhibition

Vascular miR-181b controls tissue factor-dependent thrombogenicity and inflammation in type 2 diabetes

MicroRNA‑20b promotes proliferation of H22 hepatocellular carcinoma cells by targeting PTEN

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