Significance of hypoxia-inducible factor-1α expression with atrial fibrosis in rats induced with isoproterenol

Su, Fangju; Zhang, Weize; Chen, Yongqing; Ma, Liang; Zhang, Hanping; Wang, Fei

doi:10.3892/etm.2014.1989

Cited by 26 publications

(22 citation statements)

References 28 publications

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“…Previous studies have shown that the greater vulnerability of the atrium for re-entrant arrhythmias by hypoxia is based on the combination of a moderate shortening of the wavelength and an increase in homogeneity in the conduction of premature wavefronts 18,22. Other groups have shown that MMP-9 expression and upregulation of HIF-1a/VEGF increase in fibrillating atria, which may contribute to the atrial structural remodeling seen in these patients 23–25. On the other hand, hypercapnia produces a marked and uniform increase in atrial refractoriness and a significant slowing in atrial conduction 22.…”

Section: Discussionmentioning

confidence: 99%

<p>A prospective study of the clinical outcomes and prognosis associated with comorbid COPD in the atrial fibrillation population</p>

Rodríguez‐Mañero¹,

López-Pardo²,

Cordero³

et al. 2019

COPD

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Background Patients with COPD are at higher risk of presenting with atrial fibrillation (AF). Information about clinical outcomes and optimal medical treatment of AF in the setting of COPD remains missing. We aimed to describe the prevalence of COPD in a sizeable cohort of real-world AF patients belonging to the same healthcare area and to examine the relationship between comorbid COPD and AF prognosis. Methods Prospective analysis performed in a specific healthcare area. Data were obtained from several sources within the “data warehouse of the Galician Healthcare Service” using multiple analytical tools. Statistical analyses were completed using SPSS 19 and STATA 14.0. Results A total of 7,990 (2.08%) patients with AF were registered throughout 2013 in our healthcare area (n=348,985). Mean age was 76.83±10.51 years and 937 (11.7%) presented with COPD. COPD patients had a higher mean CHA 2 DS 2 -VASc (4.21 vs 3.46; P =0.02) and received less beta-blocker and more digoxin therapy than those without COPD. During a mean follow-up of 707±103 days, 1,361 patients (17%) died. All-cause mortality was close to two fold higher in the COPD group (28.3% vs 15.5%; P <0.001). Independent predictive factors for all-cause mortality were age, heart failure, diabetes, previous thromboembolic event, dementia, COPD, and oral anticoagulation (OA). There were nonsignificant differences in thromboembolic events (1.7% vs 1.5%; P =0.7), but the rate of hemorrhagic events was significantly higher in the COPD group (3.3% vs 1.9%; P =0.004). Age, valvular AF, OA, and COPD were independent predictive factors for hemorrhagic events. In COPD patients, age, heart failure, vasculopathy, lack of OA, and lack of beta-blocker use were independent predictive factors for all-cause mortality. Conclusion AF patients with COPD have a higher incidence of adverse events with significantly increased rates of all-cause mortality and hemorrhagic events than AF patients without COPD. However, comorbid COPD was not associated with differences in cardiovascular death or stroke rate. OA and beta-blocker treatment presented a risk reduction in mortality while digoxin use exerted a neutral effect.

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Section: Discussionmentioning

confidence: 99%

<p>A prospective study of the clinical outcomes and prognosis associated with comorbid COPD in the atrial fibrillation population</p>

Rodríguez‐Mañero¹,

López-Pardo²,

Cordero³

et al. 2019

COPD

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“…Previous studies have shown that ISO can promote the expression of HIF-1α in a variety of cells, which was independent of hypoxia-like environment. In our study [46][47][48], we found that HIF-1a mediated the effect of ISO on osteoblasts to enhance the secretion of CXCL12, indicating that HIF-1a signaling of osteoblasts may mediate prostate cancer bone metastasis in response to sympathetic activation. Further studies are needed to explore the mechanism of ISO-induced HIF-1α expression in osteoblasts.…”

Section: Osteoblasts Triggered By Iso Promote Migration and Invasion mentioning

confidence: 59%

β2AR-HIF-1α-CXCL12 signaling of osteoblasts activated by isoproterenol promotes migration and invasion of prostate cancer cells

Huang

Zhang

et al. 2019

Preprint

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Background: Chronic stress is well known to promote tumor progression, however, little is known on whether neurotransmitters released after chronic stress induced sympathetic activation regulate the function of osteoblasts to affect migration and invasion of metastatic cancer cells. Methods: First, the changes in migration and invasion ability of prostate cancer cell lines PC-3 and DU145 were assessed by transwell migration assay. PC-3 and DU145 cells proliferation ability were detected by CCK-8, and HIF-1α expression of osteoblasts and the momentous proteins of epithelial-mesenchymal transition (EMT) of PC-3 and DU145 cells were examined by Western blot. Then, an analysis of the main cytokines associated with bone metastasis in osteoblasts and EMT-related biomarkers in PC-3 and DU145 cells was performed by qRT-PCR. Finally, rescue experiment was performed by using HIF-1α siRNA and inhibitor, HIF-1α overexpression plasmid, β2-adrenergic receptor (β2AR) inhibitor, CXCR4 siRNA and inhibitor. Results: In this study, isoproterenol (ISO), a non-selective β-adrenergic receptor (βAR) agonist, used as a pharmacological surrogate of sympathetic nerve activation induced by chronic stress, exhibited no direct effect on migration and invasion of PC-3 and DU145 prostate cancer cells. Whereas, osteoblasts pretreated with ISO promoted EMT and migration as well as invasion of PC-3 and DU145 cells, which was independent of promoting cell proliferation and could be inhibited by β2AR inhibitor. Mechanistically, ISO increased the secretion of CXCL12 via the β2AR-HIF-1α signaling in osteoblasts. Moreover, overexpression of HIF-1α osteoblasts promoted migration and invasion of PC-3 and DU145 cells, which was inhibited by addition of recombinant knockdown of CXCR4 in PC-3 and DU145 cells, and inhibiting CXCL12-CXCR4 signaling with LY2510924 blunted the effects of osteoblasts in response to ISO on EMT and migration as well as invasion of PC-3 and DU145 cells. Conclusions: These findings indicate that β2AR-HIF-1α-CXCL12 signaling in osteoblasts facilitates migration and invasion as well as EMT of prostate cancer cells, and may play a potential role in affecting bone metastasis of prostate cancer.

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“…Previous studies also showed that the increase in HIF-1α gene expression in the myocardium may be involved in structural changes in the myocardium, including atrial fibrosis [ 6 ]. In isoproterenol-treated rats, Su et al showed positive correlation of HIF-1α expression with the extent of myocardial fibrosis (collagen volume fraction index), which implies that HIF-1α can facilitate the expression of matrix metalloproteinase-9 (MMP-9) and TGF-β1 and thus, induce atrial fibrosis [ 7 ]. In our study, hypoxia significantly upregulated HIF-1α and profibrotic proteins expression in a time-dependent manner.…”

Section: Discussionmentioning

confidence: 99%

“…Recent reports have suggested that HIF-1 plays a role in the cardiorespiratory response to hypoxia [ 5 ]. Atrial hypoxia and the HIF pathway have been implicated in structural changes of the atria, such as cardiac fibrosis, that may lead to the development of AF [ 6 , 7 ]. It has been reported that HIF-1α gene expression increases transiently in parallel with fibrogenesis in atrial myocardium during the early response of cardiomyocytes to AF [ 6 ].…”

Section: Introductionmentioning

confidence: 99%

Role of the ROS-JNK Signaling Pathway in Hypoxia-Induced Atrial Fibrotic Responses in HL-1 Cardiomyocytes

Tsai

Yang

et al. 2021

IJMS

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By promoting atrial structural remodeling, atrial hypoxia contributes to the development of the atrial fibrillation substrate. Our study aimed to investigate the modulatory effect of hypoxia on profibrotic activity in cultured HL-1 cardiomyocytes and explore the possible signaling transduction mechanisms of profibrotic activity in vitro. Hypoxia (1% O2) significantly and time-dependently increased the expression of hypoxia-inducible factor (HIF)-1α and fibrotic marker proteins collagen I and III (COL1A and COL3A), transforming growth factor (TGF)-β1 and α-smooth muscle actin (SMA). Western blot or immunohistochemistry analysis showed that hypoxia-induced increase in COL1A and COL3A was significantly attenuated by the addition of SP600125 (a specific c-Jun N-terminal kinase [JNK] inhibitor) or expression of dominant-negative JNK before hypoxia treatment. The inhibition of hypoxia-activated phosphorylation of JNK signal components (JNK, MKK4, nuclear c-Jun and ATF-2) by pre-treatment with SP600125 could suppress hypoxia-stimulated HIF-1α upregulation and fibrotic marker proteins expression. Hypoxia significantly increased reactive oxygen species (ROS) production in cultured HL-1 atrial cells. Pre-treatment with N-acetylcysteine significantly abrogated the expression of nuclear HIF-1α, JNK transduction components and fibrotic marker proteins. Taken together, these findings indicated that the hypoxia-induced atrial profibrotic response occurs mainly via the ROS/JNK pathway, its downstream upregulation of HIF-1α and c-Jun/ATF2 phosphorylation and nuclear translocation to up-regulate the expression of fibrosis-related proteins (COL1A, COL3A, TGF-β1 and α-SMA). Our result suggests that suppression of ROS/JNK signaling pathway is a critical mechanism for developing a novel therapeutic strategy against atrial fibrillation.

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Significance of hypoxia-inducible factor-1α expression with atrial fibrosis in rats induced with isoproterenol

Cited by 26 publications

References 28 publications

<p>A prospective study of the clinical outcomes and prognosis associated with comorbid COPD in the atrial fibrillation population</p>

<p>A prospective study of the clinical outcomes and prognosis associated with comorbid COPD in the atrial fibrillation population</p>

β2AR-HIF-1α-CXCL12 signaling of osteoblasts activated by isoproterenol promotes migration and invasion of prostate cancer cells

Role of the ROS-JNK Signaling Pathway in Hypoxia-Induced Atrial Fibrotic Responses in HL-1 Cardiomyocytes

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