H19 Induces Abdominal Aortic Aneurysm Development and Progression

Li, Daniel Y.; Busch, Albert; Jin, Hong; Chernogubova, Ekaterina; Pelisek, Jaroslav; Karlsson, Jan Ch; Sennblad, Bengt; Liu, Shengliang; Lao, Shen; Hofmann, Patrick; Bäcklund, Alexandra; Eken, Suzanne M; Roy, Joy; Eriksson, Per; Dacken, Brian; Ramanujam, Deepak; Dueck, Anne; Engelhardt, Stefan; Boon, Reinier A.; Eckstein, Hans‐Henning; Spin, Joshua M.; Tsao, Philip S.; Maegdefessel, Lars

doi:10.1161/circulationaha.117.032184

Cited by 187 publications

(166 citation statements)

References 69 publications

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“…These effects may rely in the transcriptional regulation ability of H19. H19 was found to regulate the mRNA transcription via recruiting more transcription factor [30], including Foxo1 [31] and E2F [32]. Also, H19 was capable of promoting phorsphorylation and nuclear transmition of transcription factors [33], thus increasing the expression of target genes.…”

Section: Discussionmentioning

confidence: 99%

LncRNA H19 initiates microglial pyroptosis and neuronal death in retinal ischemia/reperfusion injury

Wan¹,

Su²,

Zhang³

et al. 2019

Cell Death Differ

189

159

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Ischemia-reperfusion (I/R) is a common pathology when the blood supply to an organ was disrupted and then restored. During the reperfusion process, inflammation and tissue injury were triggered, which were mediated by immunocytes and cytokines. However, the mechanisms initiating I/R-induced inflammation and driving immunocytes activation remained largely unknown. In this study, we identified long non-coding RNA (lncRNA)-H19 as the key onset of I/R-induced inflammation. We found that I/R increased lncRNA-H19 expression to significantly promote NLRP3/6 inflammasome imbalance and resulted in microglial pyroptosis, cytokines overproduction, and neuronal death. These damages were effectively inhibited by lncRNA-H19 knockout. Specifically, lncRNA-H19 functioned via sponging miR-21 to facilitate PDCD4 expression and formed a competing endogenous RNA network (ceRNET) in ischemic cascade. LncRNA H19/miR-21/PDCD4 ceRNET can directly regulate I/R-induced sterile inflammation and neuronal lesion in vivo. We thus propose that lncRNA-H19 is a previously unknown danger signals in the molecular and immunological pathways of I/R injury, and pharmacological approaches to inhibit H19 seem likely to become treatment modalities for patients in the near future based on these mechanistic findings.

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Section: Discussionmentioning

confidence: 99%

LncRNA H19 initiates microglial pyroptosis and neuronal death in retinal ischemia/reperfusion injury

Wan¹,

Su²,

Zhang³

et al. 2019

Cell Death Differ

189

159

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“…It was also not found to increase in the left ventricle, showing a high degree of tissue specificity in overall expression regulation. Many studies have identified H19 as a biomarker or driver of other cardiovascular diseases such as aortic aneurysm, smooth muscle cell apoptosis, endothelial cell aging, and ischemic heart failure (Greco et al ; Li et al ; Hofmann et al ). Our findings of tissue‐specific differences in age‐related upregulation of H19 may inform future work looking at disease initiating events in these other pathologies.…”

Section: Discussionmentioning

confidence: 99%

H19 is not hypomethylated or upregulated with age or sex in the aortic valves of mice

et al. 2019

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Epigenetic dysregulation of long noncoding RNA H19 was recently found to be associated with calcific aortic valve disease (CAVD) in humans by repressing NOTCH1 transcription. This finding offers a possible epigenetic explanation for the abundance of cases of CAVD that are not explained by any clear genetic mutation. In this study, we examined the effect of age and sex on epigenetic dysregulation of H19 and subsequent aortic stenosis. Cohorts of littermate, wild‐type C57BL/6 mice were studied at developmental ages analogous to human middle age through advanced age. Cardiac and aortic valve function were assessed with M‐mode echocardiography and pulsed wave Doppler ultrasound, respectively. Bisulfite sequencing was used to determine methylation‐based epigenetic regulation of H19, and RT‐PCR was used to determine changes in gene expression profiles. Male mice were found to have higher peak systolic velocities than females, with several of the oldest mice showing signs of early aortic stenosis. The imprinting control region of H19 was not hypomethylated with age, and H19 expression was lower in the aortic valves of older mice than in the youngest group. These results suggest that age‐related upregulation of H19 is not observed in murine aortic valves and that other factors may initiate H19‐related CAVD in humans.

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“…To induce abdominal aortic aneurysm, 9‐week‐old male mice were implanted with osmotic pumps (Alzet MODEL 2004; DURECT, Cupertino, CA) that released angiotensin II (Ang II; 1,000 ng·kg −1 ·min −1 ; Sigma, Cat#: A9525‐50MG) for 28 days, as described previously (Daugherty, Manning, & Cassis, 2000). Based on previous experience and published data (Daugherty et al, 2000; Li et al, 2018) and considering the high mortality of Ang II‐treated WT mice, four groups of mice were used as follows:‐ WT mice treated with PBS ( n = 5), KO mice treated with PBS ( n = 6), WT mice treated with Ang II ( n = 22) and KO mice treated with Ang II ( n = 12). The Ethics Committee of Peking Union Medical College approved the study protocol.…”

Section: Methodsmentioning

confidence: 99%

Meprin‐α (Mep1A) enhances TNF‐α secretion by mast cells and aggravates abdominal aortic aneurysms

Gao

Liu

Guo

et al. 2020

British J Pharmacology

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Background and Purpose:Abdominal aorticaneurysm (AAA) rupture is mainly due to elastic lamina degradation. As a metalloendopeptidase, meprin-α (Mep1A) critically modulates the activity of proteins and inflammatory cytokines in various diseases.Here, we sought to investigate the functional role of Mep1A in AAA formation and rupture. Experimental Approach: AAA tissues were detected by using real-time PCR (RT-PCR), western blotting (WB), and immunohistochemistry. Further mechanistic studies used RT-PCR, WB, and enzyme-linked immunosorbent assays. Key Results: Mep1A mediated AAA formation by regulating the mast cell (MC) secretion of TNF-α, which promoted matrix metalloproteinase (MMP) expression and apoptosis in smooth muscle cells (SMCs). Importantly, increased Mep1A expression was found in human AAA tissues and in angiotensin II-induced mouse AAA tissues. Mep1A deficiency reduced AAA formation and increased the survival rate of AAA mice. Pathological analysis showed that Mep1A deletion decreased elastic lamina degradation and SMC apoptosis in AAA tissues. Furthermore, Mep1A was expressed mainly in MCs, wherein it mediated TNF-α expression. Mep1A inhibitor actinonin significantly inhibited TNF-α secretion in MCs. TNF-α secreted by MCs enhanced MMP2 expression in SMCs and promoted SMC apoptosis. Conclusion and Implications: Taken together, these data suggest that Mep1A may be vital in AAA pathophysiology by regulating TNF-α production by MCs. Knocking out Mep1A significantly decreased AAA diameter and improved AAA stability in mice. Therefore, Mep1A is a potential new therapeutic target in the development of AAA.

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H19 Induces Abdominal Aortic Aneurysm Development and Progression

Abstract: The long noncoding RNA H19 is a novel regulator of SMC survival in abdominal aortic aneurysm development and progression. Inhibition of H19 expression might serve as a novel molecular therapeutic target for aortic aneurysm disease.

Cited by 187 publications

References 69 publications

LncRNA H19 initiates microglial pyroptosis and neuronal death in retinal ischemia/reperfusion injury

LncRNA H19 initiates microglial pyroptosis and neuronal death in retinal ischemia/reperfusion injury

H19 is not hypomethylated or upregulated with age or sex in the aortic valves of mice

Meprin‐α (Mep1A) enhances TNF‐α secretion by mast cells and aggravates abdominal aortic aneurysms

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