Deficiency of miR-409-3p improves myocardial neovascularization and function through modulation of DNAJB9/p38 MAPK signaling

Bestepe, Furkan; Fritsche, Colette; Lakhotiya, Kartik; Niosi, Carolyn E.; Ghanem, G.; Martin, Gregory L.; Pal-Ghosh, Ruma; Becker-Greene, Dakota; Weston, James A.; Hollan, Ivana; Risnes, Ivar; Rynning, S. E.; Solheim, Ludvig Fjeld; Feinberg, Mark W.; Blanton, Robert M.; Icli, Basak

doi:10.1016/j.omtn.2023.05.021

Cited by 3 publications

(8 citation statements)

References 70 publications

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“…[40][41][42] We have previously identified anti-angiomiR-409-3p as a potent regulator of angiogenesis in the setting of diet-inducedobesity, improving brown adipose angiogenesis, metabolism, and acute myocardial infarction (AMI)-associated left ventricle (LV)-dysfunction and angiogenesis. 27,28 Herein, we show for the first time that miR-409-3p and its target BTG2 play pivotal roles in cutaneous wound healing and angiogenesis under hyperglycemic conditions (Figures 6 and 7).…”

Section: Discussionmentioning

confidence: 79%

“…The genotypes of mice were confirmed by PCR genotyping of tail biopsies (Transnetyx) as previously described. 28 Male, 4 weeks old, MiR409 Ind-ECKO and MiR409 2. 16 | MiR-409-3p expression in skin of patients with nonhealing wounds and T2D…”

Section: Animal Studiesmentioning

confidence: 99%

“…26 We have previously shown that miR-409-3p acts as a potent negative regulator of angiogenesis. 27,28 MiR-409-3p expression was increased in endothelial cells (ECs) of brown adipose tissue (BAT) in obese mice. Systemic miR-409-3p neutralization was associated with improved BAT angiogenesis and insulin resistance.…”

Section: Introductionmentioning

confidence: 99%

“…We have previously shown that miR‐409‐3p acts as a potent negative regulator of angiogenesis 27,28 . MiR‐409‐3p expression was increased in endothelial cells (ECs) of brown adipose tissue (BAT) in obese mice.…”

Section: Introductionmentioning

confidence: 99%

“…Systemic miR‐409‐3p neutralization was associated with improved BAT angiogenesis and insulin resistance 27 . Additionally, EC‐specific miR‐409‐3p deletion improved angiogenesis and cardiac function after acute myocardial infarction (AMI), improving heart healing 28 . Due to ECs' prominent role in angiogenesis, we investigated the effects of EC‐specific neutralization of miR‐409‐3p in diabetic wound healing.…”

Section: Introductionmentioning

confidence: 99%

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MicroRNA‐409‐3p/BTG2 signaling axis improves impaired angiogenesis and wound healing in obese mice

Bestepe,

Ghanem,

Fritsche

et al. 2024

The FASEB Journal

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Wound healing is facilitated by neoangiogenesis, a complex process that is essential to tissue repair in response to injury. MicroRNAs are small, noncoding RNAs that can regulate the wound healing process including stimulation of impaired angiogenesis that is associated with type‐2 diabetes (T2D). Expression of miR‐409‐3p was significantly increased in the nonhealing skin wounds of patients with T2D compared to the non‐wounded normal skin, and in the skin of a murine model with T2D. In response to high glucose, neutralization of miR‐409‐3p markedly improved EC growth and migration in human umbilical vein endothelial cells (HUVECs), promoted wound closure and angiogenesis as measured by increased CD31 in human skin organoids, while overexpression attenuated EC angiogenic responses. Bulk mRNA‐Seq transcriptomic profiling revealed BTG2 as a target of miR‐409‐3p, where overexpression of miR‐409‐3p significantly decreased BTG2 mRNA and protein expression. A 3′ untranslated region (3′‐UTR) luciferase assay of BTG2 revealed decreased luciferase activity with overexpression of miR‐409‐3p, while inhibition had opposite effects. Mechanistically, in response to high glucose, miR‐409‐3p deficiency in ECs resulted in increased mTOR phosphorylation, meanwhile BTG‐anti‐proliferation factor 2 (BTG2) silencing significantly decreased mTOR phosphorylation. Endothelial‐specific and tamoxifen‐inducible miR‐409‐3p knockout mice (MiR‐409IndECKO) with hyperglycemia that underwent dorsal skin wounding showed significant improvement of wound closure, increased blood flow, granulation tissue thickness (GTT), and CD31 that correlated with increased BTG2 expression. Taken together, our results show that miR‐409‐3p is a critical mediator of impaired angiogenesis in diabetic skin wound healing.

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Section: Discussionmentioning

confidence: 79%

Section: Animal Studiesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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MicroRNA‐409‐3p/BTG2 signaling axis improves impaired angiogenesis and wound healing in obese mice

Bestepe,

Ghanem,

Fritsche

et al. 2024

The FASEB Journal

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Predictive value of circulating miR-409-3p for major adverse cardiovascular events in patients with type 2 diabetes mellitus and coronary heart disease

Cao,

Pan,

et al. 2024

Endocrinología, Diabetes y Nutrición

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Increasing serum miR-409-3p predicts the major adverse cardiac adverse events in elderly patients after hip fracture surgery

Sun,

Cheng,

Jin

et al. 2023

BMC Musculoskelet Disord

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Background Major adverse cardiovascular events (MACE) are critical complications responsible for the morbidity and mortality of elderly hip fracture patients. There was an urgent need to explore an effect biomarker for predicting MACE in elderly patients receiving hip fracture surgery. Objective This study focused on an age-related miRNA, miR-409-3p, and assessed its significance in elderly hip fracture patients. Methods A total of 267 hip fracture patients were enrolled in this study including 104 elderly patients (age ≥ 60 years). All patients were followed up for 1 year to monitor the occurrence of MACE. The risk factors for the occurrence of MACE were evaluated by the logistic regression analysis. Results Elderly age and reduced cardiac and renal function were identified as risk factors for MACE in hip fracture patients. Elderly patients also showed a high incidence of MACE. In elderly hip fracture patients, significant upregulation of miR-409-3p was observed, which was associated with patients’ elderly age, higher level of revised cardiac risk index (RCRI), lower left ventricular ejection fraction (LVEF), and higher levels of N-terminal pro-brain natriuretic peptide (NT-proBNP), creatine kinase-MB (CK-MB), and high sensitivity troponin I (hsTnI). Additionally, miR-409-3p was identified as an independent factor for the MACE in elderly patients received hip fracture surgery. Conclusion Upregulated miR-409-3p was an age-related miRNA and could predict the occurrence of MACE in elderly hip fracture patients.

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Deficiency of miR-409-3p improves myocardial neovascularization and function through modulation of DNAJB9/p38 MAPK signaling

Cited by 3 publications

References 70 publications

MicroRNA‐409‐3p/BTG2 signaling axis improves impaired angiogenesis and wound healing in obese mice

MicroRNA‐409‐3p/BTG2 signaling axis improves impaired angiogenesis and wound healing in obese mice

Predictive value of circulating miR-409-3p for major adverse cardiovascular events in patients with type 2 diabetes mellitus and coronary heart disease

Increasing serum miR-409-3p predicts the major adverse cardiac adverse events in elderly patients after hip fracture surgery

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