Association of KATP Variants With CMD and RAP in CAD Patients With Increased Serum Lipoprotein(a) Levels.

CONTEXT: Refractory angina pectoris (RAP) is a specific subtype of coronary artery disease (CAD). Lipoprotein(a) [Lp(a)] and its induced coronary microvascular dysfunction (CMD) play an important role in pathogenesis of RAP, but its metabolism was mostly genetically determined. The adenosine triphosphate (ATP)-sensitive potassium channel (KATP) is involved in lipid metabolism and microvascular homeostasis and becomes a promising target for the management of Lp(a) and its related RAP. OBJECTIVE: To investigate associations of KATP variants with hyperlipoprotein(a)emia, CMD, and RAP in patients with CAD. DESIGN, PATIENTS, SETTINGS: A total of 1148 newly diagnosed patients with CAD were prospectively selected and divided into control (Lp(a) < 180 mg/dL) and case (Lp(a) ≥ 180 mg/dL, hyperlipoprotein(a)emia) group. METHODS: 9 KATP variants were genotyped by MassARRAY system. The expression profile of exosome-derived microRNAs (exo-miRs) was identified by next-generation sequencing, and the expression levels of differentially expressed exo-miRs were evaluated by quantitative RT-PCR in verification cohort. RESULTS: Three KATP variants were associated with increased risk of hyperlipoprotein(a)emia in patients with CAD as follows: rs2285676 (AA + GA genotype, adjusted odds ratio [OR] = 1.44; 95% CI, 1.10-1.88; P = 0.008), rs1799858 (CC genotype, adjusted OR = 1.33; 95% CI, 1.03-1.73; P = 0.030), and rs141294036 (CC genotype, adjusted OR = 1.43; 95% CI, 1.10-1.87; P = 0.008). Only rs141294036 was associated with increased risk of CMD (CC genotype, adjusted OR = 1.62; 95% CI, 1.23-2.13; P = 0.001), and further with increased RAP risk (CC genotype, adjusted hazard ratio = 2.05; 95% CI, 1.22-3.43; P = 0.007) after median follow-up of 50.6 months. Between the 2 genotypes of rs141294036, 152 exo-miRs were significantly differentially expressed, but only 10 exo-miRs (miR-7110-3p, miR-548az-5p, miR-214-3p, let-7i-5p, miR-218-5p, miR-128-3p, miR-378i, miR-625-3p, miR-128-1-5p, and miR-3187-3p) were further confirmed in patients with RAP with hyperlipoprotein(a)emia and CMD. CONCLUSION: KATP rs141294036 may serve a potential genetic marker for hyperlipoprotein(a)emia, CMD, and RAP in patients with CAD.

Association of marital status with cardiovascular outcome in patients with breast cancer.

Background: The influences of marital status on cardiovascular death risk in patients with breast cancer remained unclear. This study aimed to evaluate the associations of different marital status with cardiovascular death risk in patients with breast cancer. Methods: A total of 182,666 female breast cancer patients were enrolled in this study from the Surveillance, Epidemiology, and End Results (SEER) database from 2010 to 2014, and was divided into two groups: married (N=107,043) and unmarried (N=75,623). A 1:1 propensity score matching (PSM) was applied to reduce inter-group bias between the two groups. Competing-risks model was used to assess the associations between different marital status and cardiovascular death risk in patients with breast cancer. Results: After PSM, marital status was an independent predictor for cardiovascular death in patients with breast cancer. Unmarried condition was associated with increased cardiovascular death risk than married condition among breast cancer patients [unadjusted model: hazard ratio (HR) =2.012, 95% confidence interval (CI): 1.835-2.208, P<0.001; Model 1: HR =1.958, 95% CI: 1.785-2.148, P<0.001; Model 2: HR =1.954, 95% CI: 1.781-2.144, P<0.001; Model 3: HR =1.920, 95% CI: 1.748-2.107, P<0.001]. With the exception of separated condition (adjusted HR =0.886, 95% CI: 0.474-1.658, P=0.705), further unmarried subgroups analysis showed that the other three unmarried status were associated with increased cardiovascular death risk as follows: single (adjusted HR =1.623, 95% CI: 1.421-1.853, P<0.001), divorced (adjusted HR =1.394, 95% CI: 1.209-1.608, P<0.001), and widowed (adjusted HR =2.460, 95% CI: 2.227-2.717, P<0.001). In particularly, widowed condition showed the highest cardiovascular death risk in all 4 unmarried subgroups. Conclusions: Unmarried condition (e.g., single, divorced and widowed) was associated with elevated cardiovascular death risk compared with their married counterparts in patients with breast cancer, suggesting that more attention and humanistic care should be paid to unmarried breast cancer patients (especially the widowed patients) in the management of female breast cancer patients.

CircRNA Chordc1 protects mice from abdominal aortic aneurysm by contributing to the phenotype and growth of vascular smooth muscle cells.

Circular RNAs (circRNAs) have important potential in modulating vascular smooth muscle cell (VSMC) activity, but their roles in abdominal aortic aneurysm (AAA) are unknown. We performed in situ hybridization and immunohistochemistry and determined that circChordc1 (cysteine and histidine-rich domain containing 1) was markedly downregulated in aneurysm tissue compared with normal arteries. A gene gain and loss strategy was used to confirm that circChordc1 transformed VSMCs into a contracted phenotype and improved their growth, which significantly suppressed aneurysm formation and reduced the risk of rupture in mouse models of angiotensin (Ang) II- and CaCl2-induced AAA. RNA pull-down, immunoprecipitation, and immunoblotting indicated that circChordc1 facilitated the VSMC phenotype and growth determination by binding to vimentin and ANXA2 (annexin A2), which not only increased vimentin phosphorylation to promote its degradation but also promoted the interaction between ANXA2 and glycogen synthase kinase 3 beta (GSK3ß) to induce the nuclear entry of ß-catenin. Thus, our present study revealed that circChordc1 optimized the VSMC phenotype and improved their growth by inducing vimentin degradation and increasing the activity of the GSK3ß/ß-catenin pathway, thereby extenuating vascular wall remodeling and reversing pathological aneurysm progression.

Clinical and Genetic Analysis of KATP Variants With Heart Failure Risk in Patients With Decreased Serum ApoA-I Levels.

CONTEXT: Lower serum concentration of apolipoprotein A-I (ApoA-I) is causally associated with heart failure (HF) risk. Adenosine triphosphate-sensitive potassium channels (KATP), as gating channels coupling vascular reactivity and metabolism with ischemic protection, become a new potential target of management for HF. The KATP gene sequence is highly polymorphic and has a high degree of genetic heterogeneity. OBJECTIVE: This work aimed to determine whether KATP variants predict the risks of decreased ApoA-I concentration and its related HF. METHODS: A total of 634 individuals, including 317 patients with decreased ApoA-I concentration (< 120 mg/dL) and 317 counterpart participants (≥ 120 mg/dL), were retrospectively selected. Five KATP variants were genotyped through the MassARRAY platform. Exosome-derived microRNAs (exo-miRs) expression profiles were identified by next-generation sequencing, and the top 10 differentially expressed (DE) exo-miRs were verified using quantitative polymerase chain reaction in a validation cohort of 240 individuals with decreased ApoA-I concentration. RESULTS: KATP rs141294036 was related to an increased risk of lower ApoA-I levels (adjusted odds ratio [OR] = 1.95, P = .002) and HF incidence (adjusted OR = 2.38, P = .009), especially heart failure with preserved ejection fraction (HFpEF; adjusted OR = 2.13, P = .015). After a median 48.6-month follow-up, participants carrying the CC genotype of rs141294036 were associated with an elevated HF rehospitalization risk (adjusted hazard ratio = 1.91, P = .005). Thirty-six exo-miRs were significantly DE between different genotypes of rs141294036 in participants with lower ApoA-I levels, but only 5 exo-miRs (miR-31-5p, miR-126-5p, miR-106a-5p, miR-378i, and miR-181c-5p) were further confirmed. CONCLUSION: KATP rs141294036 was associated with increased risks of lower ApoA-I levels, HF incidence (especially HFpEF), and HF rehospitalization in those with the 5 confirmed exo-miRs and its related metabolic pathways.

Cardiovascular Death Risk in Primary Central Nervous System Lymphoma Patients Treated With Chemotherapy: A Registry-Based Cohort Study.

PURPOSE: To study the cardiovascular death (CVD) risk in primary central nervous system lymphoma (PCNSL) patients with chemotherapy. METHODS: We obtained 2,020 PCNSL participants and 88,613 non-central nervous system lymphoma (NCNSL) participants with chemotherapy from Surveillance, Epidemiology, and End Results (SEER) database from 2004 to 2015. A 1:3 propensity score matching (PSM) was used to reduce the imbalance between PCNSL participants with and without chemotherapy, as well as the imbalance between PCNSL and NCNSL participants with chemotherapy. Competing risks regressions were conducted to evaluate the independent influence of chemotherapy on CVD. RESULTS: After 1:3 PSM, the CVD risk in PCNSL patients with chemotherapy was lower than those without chemotherapy [decreased 53%, adjusted HR, 0.469 (95% CI, 0.255-0.862; P = 0.015)] as well as NCNSL patients with chemotherapy [decreased 36%, adjusted HR in model 1, 0.636 (95% CI, 0.439-0.923; P = 0.017)]. The CVD risk of chemotherapy decreased in PCNSL patients with age at diagnosis >60 years old [adjusted HR, 0.390 (95% CI, 0.200-0.760; P = 0.006)], and those patients diagnosed at 2010 to 2015 [adjusted HR, 0.339 (95% CI, 0.118-0.970; P = 0.044)]. CONCLUSION: PCNSL patients with chemotherapy are associated with lower CVD risk. Our findings may provide new foundations for that chemotherapy is the first-line treatment for PCNSL patients, according to a cardiovascular risk perspective.

Hydrogen sulfide-loaded microbubbles combined with ultrasound mediate thrombolysis and simultaneously mitigate ischemia-reperfusion injury in a rat hindlimb model.

BACKGROUND: Thromboembolism and subsequent ischemia/reperfusion injury (IRI) remain major clinical challenges. OBJECTIVES: To investigate whether hydrogen sulfide (H2 S)-loaded microbubbles (hs-Mbs) combined with ultrasound (US) radiation (hs-Mbs+US) dissolve thrombi and simultaneously alleviate tissue IRI through local H2 S release. METHODS: hs-Mbs were manufactured and US-triggered H2 S release was recorded. White and red thromboembolisms were established ex vivo and in rats left iliac artery. All subjects randomly received control, US, Mbs+US, or hs-Mbs+US treatment for 30 minutes. RESULTS: H2 S was released from hs-Mbs+US both ex vivo and in vivo. Compared with control and US, hs-Mbs+US and Mbs+US showed comparable substantial decreases in thrombotic area, clot mass, and flow velocity increases for both ex vivo macrothrombi. In vivo, hs-Mbs+US and Mbs+US caused similarly increased recanalization rates, blood flow velocities, and hindlimb perfusion for both thrombi compared with the other treatments, with no obvious influence on hemodynamics, respiration, and macrophage vitality. More importantly, hs-Mbs+US substantially alleviated skeletal muscle IRI by reducing reactive oxygen species, cellular apoptosis, and proapoptotic Bax, caspase-3, and caspase-9 and increasing antiapoptotic Bcl-2 compared with other treatments. In vitro, hypoxia/reoxygenation-predisposed skeletal muscle cells and endothelial cells treated with normal saline solution exhibited similar trends, which were largely reversed by an H2 S scavenger or an inhibitor of Akt phosphorylation. CONCLUSION: hs-Mbs+US effectively dissolved both white and red macrothrombi and simultaneously alleviated skeletal muscle IRI through the US-triggered, organ-specific release of H2 S. This integrated therapeutic strategy holds promise for treating thromboembolic diseases and subsequent IRI.

Itaconate prevents abdominal aortic aneurysm formation through inhibiting inflammation via activation of Nrf2.

BACKGROUND: Identifying effective drugs to suppress vascular inflammation is a promising strategy to delay the progression of abdominal aortic aneurysm (AAA). Itaconate has a vital role in regulating inflammatory activation in various inflammatory diseases. However, the role of itaconate in the progression of AAA is unknown. In this study, we explored the inhibitory effect of itaconate on AAA formation and its underlying mechanisms. METHODS: Quantitative PCR, western blotting and immunohistochemistry were used to determine Irg1 and downstream Nrf2 expression in human and mouse AAA samples. Liquid chromatograph-mass spectrometry (LC-MS) analysis was performed to measure the abundance of itaconate. OI treatment and Irg1 knockdown were performed to study the role of OI in AAA formation. Nrf2 intervention in vivo was performed to detect the critical role of Nrf2 in the beneficial effect of OI on AAA. FINDINGS: We found that itaconate suppressed the formation of angiotensin II (Ang II)-induced AAA in apolipoprotein E-deficient (Apoe-/-) mice, while Irg1 deficiency exerted the opposite effect. Mechanistically, itaconate inhibited vascular inflammation by enabling Nrf2 to function as a transcriptional repressor of downstream inflammatory genes via alkylation of Keap1. Moreover, Nrf2 deficiency significantly aggravated inflammatory factor expression and promoted AAA formation. In addition, Keap1 overexpression significantly promoted Ang II-induced AAA formation, which was inhibited by itaconate. INTERPRETATION: Itaconate inhibited AAA formation by suppressing vascular inflammation, and therapeutic approaches to increase itaconate are potentially beneficial for preventing AAA formation. FUNDING: National Natural Science Foundations of China and Guangzhou regenerative medicine and Health Laboratory of Guangdong.

Prognostic Impacts of Tumour Size on Patients With Primary Cardiac Sarcoma.

BACKGROUND: Primary cardiac sarcoma (PCS) is a deadly disease. The impacts of tumour size on prognosis and surgical outcomes in PCS patients remains unclear. Here, we evaluate the impact of tumour size on overall survival (OS) and cancer-specific survival (CSS) of PCS patients to provide a reference for the surgical treatment. METHODS: A total of 261 PCS participants enrolled from 1983 to 2016 were identified from the Surveillance, Epidemiology, and End Results database. Using the X-tile program, we classified the tumour size into 2 subgroups: ≤ 4.0 cm and > 4.0 cm. The Kaplan-Meier method was used to determine OS and CSS. Univariate and multivariate Cox regression analyses were used to identify the independent prognostic impacts of tumour size and surgery in the 2 subgroups (≤ 4.0 cm vs > 4.0 cm). RESULTS: With the use of 4.0 cm as a cutoff value, tumour size seemed to be an independent prognostic factor for OS (P = 0.009) and CSS (P = 0.014) of PCS patients. Surgery improved the OS (P = 0.017) and CSS (P = 0.040) in PCS patients with tumour size > 4.0 cm but not in with tumour size ≤ 4.0 cm (both P > 0.05). CONCLUSIONS: Tumour size of > 4.0 cm is an independent predictor of poor prognosis and is associated with the surgical outcomes in PCS patients. Surgery significantly improves the prognosis in PCS patients with tumour size > 4.0 cm. Our findings have the potential to assist clinicians to better evaluate the prognosis of PCS patients and develop optimal therapeutic strategies.

Increased Risk of Cardiovascular Death in Breast Cancer Patients Without Chemotherapy or (and) Radiotherapy: A Large Population-Based Study.

BACKGROUND: Cardiovascular death (CVD) in breast cancer patients without chemotherapy (CT) or (and) radiotherapy (RT) has not been studied yet. This study evaluates the correlation between breast cancer and CVD risk independent of chemotherapy or (and) radiotherapy. METHODS: Data of female breast cancer patients without receiving CT or RT were retrieved from the Surveillance, Epidemiology, and End Result (SEER) database (2004-2015). Data were divided into two cohorts: tumor resection cohort and no resection cohort. The CVD risk in patients was expressed as standardized mortality ratios (SMRs). A 1:1 propensity score matching (PSM) was applied to balance inter-group bias, and competing risk regressions were utilized to evaluate the impact of tumor resection on CVD. RESULTS: The CVD risk was significantly higher (SMR = 2.196, 95% CI: 2.148-2.245, P<0.001) in breast cancer patients who did not receive CT or RT compared to the general population. Breast cancer patients without tumor resection showed higher CVD risk than patients who underwent tumour resection (tumor resection SMR = 2.031, 95% CI: 1.983-2.079, P<0.001; no resection SMR = 5.425, 95% CI: 5.087-5.781, P<0.001). After PSM, the CVD risk among patients without tumor resection indicated an increase of 1.165-fold compared to patients with tumor resection (HR=1.165, 95% CI: 1.039-1.306, P=0.009). CONCLUSIONS: Female breast cancer patients are at higher risk of CVD despite unexposure to cardio-toxic CT or RT. However, female breast cancer patients subjected to tumor resection have decreased CVD risk. These results indicated that monitoring female breast cancer patients not receiving RT or CT might serve as a preventative measure against CVD.

Nomograms and risk classification systems predicting overall and cancer-specific survival in primary malignant cardiac tumor.

BACKGROUND: Primary malignant cardiac tumors (PMCTs) are fatal, but up to now, there is still a lack of survival prediction model for prognosis evaluation. We developed nomograms to predict overall survival (OS) and cancer-specific survival (CSS) for PMCTs by the Surveillance, Epidemiology, and End Result (SEER) database. METHODS: A total of 506 PMCTs participants were identified in the SEER database from 1973 to 2014 and were randomly assigned into the training cohort (N = 354) and the validation cohort (N = 152). The prognostic factors for PMCTs were identified by Kaplan-Meier and multivariate Cox analysis and further incorporated to build OS and CSS nomograms. The nomograms were internally and externally validated via concordance indexes (C-index) and calibration curves. RESULTS: The independent prognostic factors for OS and CSS in PMCTs were associated with age at diagnosis, histopathology, tumor stage, cancer-directed surgery, and chemotherapy (all P < .05). In the internal validation, the C-index values were 0.71 (95% confidence interval [CI]: 0.68-0.75) for OS nomogram, and 0.70 (95% CI: 0.67-0.74) for CSS nomogram. In the external validation, the C-index values were 0.71 (95% CI: 0.66-0.77) for OS nomogram, and 0.71 (95% CI: 0.65-0.77) for CSS nomogram. The calibration curves of internal and external validation showed consistency between the nomograms and the actual observation. The risk stratification of PMCTs was significant distinction (P < .05). CONCLUSION: We developed and validated credible nomograms to predict OS and CSS in PMCTs. These nomograms can be offered to clinicians to more precisely estimate the survival and identify risk stratification of PMCTs.

Long noncoding RNA GAS5 induces abdominal aortic aneurysm formation by promoting smooth muscle apoptosis.

Objective: Long noncoding RNAs (lncRNAs) may serve as specific targets for the treatment of abdominal aortic aneurysms (AAAs). LncRNA GAS5, functionally associated with smooth muscle cell (SMC) apoptosis and proliferation, is likely involved in AAA formation, but the exact role of GAS5 in AAA is unknown. We thus explored the contribution of GAS5 to SMC-regulated AAA formation and its underlying mechanisms. Methods: Human specimens were used to verify the diverse expression of GAS5 in normal and AAA tissues. The angiotensin II (Ang II)-induced AAA model in ApoE-/- mice and the CaCl2-induced AAA model in wild-type C57BL/6 mice were used. RNA pull-down and luciferase reporter gene assays were performed in human aortic SMCs to detect the interaction between GAS5 and its downstream targets of protein or microRNA (miR). Results: GAS5 expression was significantly upregulated in human AAA specimens and two murine AAA models compared to human normal aortas and murine sham-operated controls. GAS5 overexpression induced SMC apoptosis and repressed its proliferation, thereby promoting AAA formation in two murine AAA models. Y-box-binding protein 1 (YBX1) was identified as a direct target of GAS5 while it also formed a positive feedback loop with GAS5 to regulate the downstream target p21. Furthermore, GAS5 acted as a miR-21 sponge to release phosphatase and tensin homolog from repression, which blocked the activation and phosphorylation of Akt to inhibit proliferation and promote apoptosis in SMCs. Conclusion: The LncRNA GAS5 contributes to SMC survival during AAA formation. Thus, GAS5 might serve as a novel target against AAA.

The pseudogene PTENP1 regulates smooth muscle cells as a competing endogenous RNA.

The long non-coding RNA (lncRNA) PTENP1 is a pseudogene of phosphatase and tensin homologue deleted on chromosome ten (PTEN), has been implicated in smooth muscle cell (SMC) proliferation and apoptosis. PTENP1 is the pseudogene of PTEN. However, it is unclear whether and how PTENP1 functions in the proliferation and apoptosis of human aortic SMCs (HASMCs). Here, we hypothesised that PTENP1 inhibits HASMC proliferation and enhances apoptosis by promoting PTEN expression. PCR analysis and Western blot assays respectively showed that both PTENP1 and PTEN were up-regulated in human aortic dissection (AD) samples. PTENP1 overexpression significantly increased the protein expression of PTEN, promoted apoptosis and inhibited the proliferation of HASMCs. PTENP1 silencing exhibited the opposite effects and mitigated H2O2-induced apoptosis of HASMCs. In an angiotensin II (Ang II)-induced mouse aortic aneurysm (AA) model, PTENP1 overexpression potentiated aortic SMC apoptosis, exacerbated aneurysm formation. Mechanistically, RNA pull-down assay and a series of luciferase reporter assays using miR-21 mimics or inhibitors identified PTENP1 as a molecular sponge for miR-21 to endogenously compete for the binding between miR-21 and the PTEN transcript, releasing PTEN expression. This finding was further supported by in vitro immunofluorescent evidence showing decreased cell apoptosis upon miR-21 mimic administration under baseline PTENP1 overexpression. Ex vivo rescue of PTEN significantly mitigated the SMC apoptosis induced by PTENP1 overexpression. Finally, Western blot assays showed substantially reduced Akt phosphorylation and cyclin D1 and cyclin E levels with up-regulated PTENP1 in HASMCs. Our study identified PTENP1 as a mediator of HASMC homeostasis and suggests that PTENP1 is a potential target in AD or AA intervention.

LncRNA H19 promotes vascular inflammation and abdominal aortic aneurysm formation by functioning as a competing endogenous RNA.

Abdominal aortic aneurysm (AAA) is accepted as a chronic vascular inflammatory disease. However, how the inflammatory response is regulated during AAA formation is not fully understood. This study was undertaken to determine whether the long noncoding RNA (lncRNA) H19 (H19) promotes AAA formation by enhancing aortic inflammation. qRT-PCR detected the upregulation of H19 in human and mouse AAA tissue samples. Co-staining for H19 and the macrophage marker MAC-2 showed that H19 was located in vascular smooth muscle cells (VSMCs) and infiltrating aortic macrophages. In vivo overexpression of H19 increased vascular inflammation and induced AAA formation, which was supported by exacerbated aortic morphology, maximum aortic diameter values, elastin degradation, expression of interleukin-6 (IL-6) and macrophage chemoattractant protein-1 (MCP-1), and macrophage infiltration. H19 suppression resulted in the opposite effects. A rescue experiment indicated that IL-6 neutralization significantly mitigated the aortic inflammation and AAA formation evoked by H19 overexpression. Luciferase reporter assays and ex vivo experiments using VSMCs and macrophages confirmed that H19 induced aneurysm formation in part via endogenous competition with the let-7a microRNA to induce the transcription of its target gene, IL-6. This mechanism was further validated by in vivo experiments using a mutant H19 that could not effectively bind let-7a. Collectively, our study revealed a pathogenic H19/let-7a/IL-6 inflammatory pathway in AAA formation, which offers a new potential therapeutic strategy for AAA.

Mutant hypoxia inducible factor-1α improves angiogenesis and tissue perfusion in ischemic rabbit skeletal muscle.

Hypoxia-inducible factor-1α (HIF-1α) is one of the most potent angiogenic growth factors. It regulates genes involved in angiogenesis, but is inactivated rapidly by normoxia. Ad-HIF-1α-Trip was constructed by transforming Pro402, Pro564, and Asn803 in HIF-1α to alanine in order to delay degradation and create a constitutive transcriptional activator. In this study, we investigated whether Ad-HIF-1α-Trip could induce functional mature angiogenesis and the possible mechanisms involved. We found that Ad-HIF-1α-Trip increased the expression of multiple angiogenic genes in cultured HMVEC-Ls, including VEGF, PLGF, PAI-1, and PDGF. In a rabbit model of acute hind limb ischemia, Ad-HIF-1α-Trip improved tissue perfusion and collateral vessels, as measured by contrast-enhanced ultrasound (CEU), CT angiography, and vascular casting. Ad-HIF-1α-Trip also produced more histologically identifiable capillaries, which were verified by immunostaining, compared with controls. Interestingly, inhibition of CBP/p300 by curcumin prevented HIF-1α from inducing the expression of several angiogenic genes. The present study suggests that Ad-HIF-1α-Trip can induce mature angiogenesis and improve tissue perfusion in ischemic rabbit skeletal muscle. CBP/p300, which interacts with the transactivation domains of HIF-1α, is important for HIF-1α-induced transcription of angiogenic genes.