Hypoxia-inducible factor-1a (HIF-1a) is a principal regulator of angiogenesis and other cellular responses to hypoxic stress in both normal and tumor cells. To identify novel mechanisms that regulate expression of HIF-1a, we designed a genome-wide screen for expressed sequence tags (ESTs) that when transcribed in the antisense direction increase production of the HIF-1a target, vascular endothelial growth factor (VEGF), in human breast cancer cells. We discovered that heat shock factor (HSF) proteins 2 and 4-which previously have been implicated in the control of multiple genes that modulate cell growth and differentiation and protect against effects of environmental and cellular stresses-function together to maintain a steady state level of HIF-1a transcription and VEGF production in these cells. We show both HSFs bind to discontinuous heat shock element (HSE) sequences we identified in the HIF-1a promoter region and that downregulation of either HSF activates transcription of HIF-1a. We further demonstrate that HSF2 and HSF4 displace each other from HSF/HSE complexes in the HIF-1a promoter so that HIF-1a transcription is also activated by overexpression of either HSFs. These results argue that HSF2 and HSF4 regulate transcription of HIF-1a and that a critical balance between these HSF is required to maintain HIF-a expression in a repressed state. Our findings reveal a previously unsuspected role for HSFs in control of VEGF and other genes activated by canonical HIF-1a-mediated signaling.
Background Clean Cut is an adaptive, multimodal programme to identify improvement opportunities and safety changes in surgery by enhancing outcomes surveillance, closing gaps in surgical infection prevention standards, and strengthening underlying processes of care. Surgical-site infections (SSIs) are common in low-income countries, so this study assessed a simple intervention to improve perioperative infection prevention practices in one. Methods Clean Cut was implemented in five hospitals in Ethiopia from August 2016 to October 2018. Compliance data were collected from the operating room focused on six key perioperative infection prevention standards. Process-mapping exercises were employed to understand barriers to compliance and identify locally driven improvement opportunities. Thirty-day outcomes were recorded on patients for whom intraoperative compliance information had been collected. Results Compliance data were collected from 2213 operations (374 at baseline and 1839 following process improvements) in 2202 patients. Follow-up was completed in 2159 patients (98·0 per cent). At baseline, perioperative teams complied with a mean of only 2·9 of the six critical perioperative infection prevention standards; following process improvement changes, compliance rose to a mean of 4·5 (P < 0·001). The relative risk of surgical infections after Clean Cut implementation was 0·65 (95 per cent c.i. 0·43 to 0·99; P = 0·043). Improved compliance with standards reduced the risk of postoperative infection by 46 per cent (relative risk 0·54, 95 per cent c.i. 0·30 to 0·97, for adherence score 3–6 versus 0–2; P = 0·038). Conclusion The Clean Cut programme improved infection prevention standards to reduce SSI without infrastructure expenses or resource investments.
AimsE-cigarette aerosol containing aldehydes, including acetaldehyde, are metabolized by the enzyme aldehyde dehydrogenase 2 (ALDH2). However, little is known how aldehyde exposure from e-cigarettes, when coupled with an inactivating ALDH2 genetic variant, ALDH2*2 (present in 8% of the world population), affects cardiovascular oxidative stress. The aim of this study was to determine how e-cigarette aerosol exposure, when coupled with genetics, impacts cardiovascular oxidative stress in wild type ALDH2 and ALDH2*2 knock-in mice.Methods and ResultsUsing selective ion flow mass spectrometry, we determined that e-cigarette aerosol contains acetaldehyde that are 10-fold higher than formaldehyde or acrolein. Next, using wild type ALDH2 and ALDH2*2 knock-in rodents, we identified organ-specific differences in ALDH2 with the heart having ~1.5-fold less ALDH2 enzyme activity relative to the liver and lung. In isolated cardiac myocytes, acetaldehyde exposure (30 seconds, 0.1-1 μM) caused a 4-fold greater peak in calcium levels for ALDH2*2 relative to ALDH2 cardiomyocytes. ALDH2*2 cardiomyocytes exposed to acetaldehyde also demonstrated a 2-fold increase in ROS production and 2.5-fold increase in 4HNE protein adducts relative to ALDH2 cardiomyocytes. For intact rodents, ALDH2*2 knock-in mice exposed to e-cigarette aerosol had an increased heart rate beginning 5 days after exposure compared to wild type ALDH2 mice (775±30 bpm versus 679±33 bpm, respectively, *p<0.01, n=7-8/group). E-cigarette aerosol exposure also exacerbated oxidative stress in ALDH2*2 heart homogenates, including a 1.3-fold higher protein carbonyl level, a 1.7-fold higher lipid peroxide level and 1.5-fold greater phosphorylation of NF-κB relative to wild type ALDH2 homogenates.ConclusionsThe increased oxidative stress from e-cigarette aerosol aldehydes triggers the proinflammatory NF-κB pathway. As ALDH2 expression and activity is lower in the heart relative to the lung, the heart could be more susceptible to increases in cardiovascular oxidative stress from e-cigarette aerosol; particularly for those carrying an ALDH2*2 genetic variant which limits acetaldehyde metabolism.Graphical AbstractE-cigarette aerosol exposure triggers increases in ROS that lead to increased protein carbonylation, MDA production, and elevates phosphorylated NF-kB. This exposure to e-cigarette aerosol leads to increases in cardiovascular oxidative stress. For the ALDH2*2 variant, there is limited ability to metabolize the reactive aldehydes from e-cigarette aerosol and with increased levels of oxidative stress at baseline relative to wild type ALDH2, e-cigarette aerosol increased oxidative stress, protein carbonylation, and phosphorylation of NF-kB relative to wild type ALDH2 rodents.
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