Protein kinase C binding protein 1 inhibits hypoxia-inducible factor-1 in the heart.

AIMS: Hypoxia-inducible factor-1 alpha (HIF-1α) is a key transcription factor responsible for the induction of genes that facilitate adaptation to hypoxia. To study HIF-1 signalling in the heart, we developed a mouse model in which an oxygen-stable form of HIF-1α can be inducibly expressed in cardiac myocytes, under the regulation of tetracycline. METHODS AND RESULTS: Remarkably, expression of the transgene in mice generated two distinct phenotypes. One was the expected expression of HIF-regulated transcripts and associated changes in cardiac angiogenesis and contractility. The other was an unresponsive phenotype with much less expression of typical HIF-response genes and substantial expression of a zinc-finger protein, Protein Kinase C Binding Protein 1 (PRKCBP1). We have demonstrated that this second phenotype is due to an insertion of a fragment of DNA upstream of the PRKCBP1 gene that contains two additional canonical HIF binding sites and leads to substantial HIF binding, assessed by chromatin immunoprecipitation, and transcriptional activation. This insertion is found only in the FVB strain of mice that contributed the αMHC-tet binding protein transgene to these biallelic mice. In HEK293 cells transfected with oxygen-stable HIF-1α and PRKCBP1, we demonstrated inhibition of HIF-1 activity by a luciferase reporter assay. Using mouse primary cells and cell lines, we show that transfection with oxygen-stable HIF-1α and PRKCBP1 reduced expression of direct HIF-1 gene targets and that knockdown of PRKCBP1 removes that negative inhibition. Consistent with previous reports suggesting that PRKCBP1 modulates the chromatin landscape, we found that HL-1 cells transfected with oxygen-stable HIF-1α and PRKCBP1 have reduced global 5-methyl cytosine compared to HIF-1 alone. CONCLUSION: We show genetic, transcriptional, biochemical, and physiological evidence that PRKCBP1 inhibits HIF activity. Identification of a new oxygen-dependent and previously unsuspected regulator of HIF may provide a target for new therapeutic approaches to ischaemic heart disease.

Myocardial perfusion pattern for stratification of ischemic mitral regurgitation response to percutaneous coronary intervention.

OBJECTIVE: Ischemic mitral regurgitation (MR) is common, but its response to percutaneous coronary intervention (PCI) is poorly understood. This study tested the utility of myocardial perfusion imaging (MPI) for the stratification of MR response to PCI. METHODS: MPI and transthoracic echocardiography (echo) were performed among patients undergoing PCI. MPI was used to assess stress/rest myocardial perfusion. MR was assessed via echo (performed before and after PCI). RESULTS: A total of 317 patients with abnormal myocardial perfusion on MPI underwent echo 25±39 days before PCI. MR was present in 52%, among whom 24% had advanced (≥moderate) MR. MR was found to be associated with left ventricular (LV) chamber dilation on MPI and echo (both P<0.001). The magnitude of global LV perfusion deficits increased in relation to MR severity (P<0.01). Perfusion differences were greatest for global summed rest scores, which were 1.6-fold higher among patients with advanced MR versus those with mild MR (P=0.004), and 2.4-fold higher versus those without MR (P<0.001). In multivariate analysis, advanced MR was found to be associated with a fixed perfusion defect size on MPI [odds ratio 1.16 per segment (confidence interval 1.002-1.34), P=0.046], independent of LV volume [odds ratio 1.10 per 10 ml (confidence interval 1.04-1.17), P=0.002]. Follow-up via echo (1.0±0.6 years) demonstrated MR to decrease (≥1 grade) in 31% of patients and increase in 12% of patients. Patients with increased MR after PCI had more severe inferior perfusion defects on baseline MPI (P=0.028), whereas defects in other distributions and LV volumes were similar (P=NS). CONCLUSION: The extent and distribution of single-photon emission computed tomography-evidenced myocardial perfusion defects impact MR response to revascularization. An increased magnitude of inferior fixed perfusion defects predicts post-PCI progression of MR.

Outcomes of metallic biliary stent insertion in patients with malignant bilobar obstruction.

PURPOSE: To assess clinical outcomes of metal stent insertion in patients with bilobar bile duct obstruction by malignant tumors. MATERIALS AND METHODS: Records of 120 consecutive patients who underwent placement of metallic stents for palliation of malignant bilobar biliary obstruction between 1995 and 2010 were retrospectively reviewed. Single-duct stent insertion was performed in 44 patients with one liver lobe that accounted for more than 70% of total liver volume or only one patent lobar portal vein (group 1). Bilobar stent insertion was performed in 60 patients with approximately equal lobe sizes, patent lobar portal veins, or cholangitis at presentation (group 2). In 16 patients with discontiguous right anterior and posterior segmental ducts (group 3), three stents were deployed in the left lobar and right anterior and posterior segmental ducts. Overall survival, primary patency, and patient morbidity rates following stent insertion were assessed. RESULTS: No significant differences in mean overall survival (group 1, 7.3 mo; group 2, 10.3 mo; group 3, 6.5 mo; P = .21) or mean primary stent patency (group 1, 4.2 mo; group 2, 5.9 mo; group 3, 3.5 mo; P = .17) were demonstrated. However, patients in group 3 were significantly more likely to require hospitalizations for cholangitis and additional invasive procedures for recurrent biliary obstruction than patients in groups 1 and 2. CONCLUSIONS: Unilobar and bilobar metal stent insertion led to similar outcomes when treatment decision was based on relative liver lobe volumes, lobar portal vein patency, and presence of cholangitis on presentation.

Lymphoma diagnosed at inguinal hernia repair.

Tumors presenting in the inguinal hernia sac are considered to be extremely rare, with the more common neoplasms metastasizing from the gastrointestinal tract, ovary and prostate. We report the case of Mantle cell lymphoma identified in the inguinal hernia sac following hernia repair While the hernia sac appeared normal to the surgeon, evaluation by the pathologist showed subtle gross irregularities, with subsequent histologic and immunochemical diagnosis of Mantle cell lymphoma. Twelve previous cases of a lymphoma diagnosed during hernia repair have been described in the English literature. This is the first report of Mantle cell lymphoma found in the hernia sac. This case illustrates the value of routine microscopic evaluation of hernia sacs found from inguinal/femoral herniorrhaphies, as it may be the primary presentation of an asymptomatic metastatic lymphoma. Additionally it underscores the importance of the surgeon's role in screening hernia sacs if the practice of submitting only macroscopically abnormal specimens for microscopic evaluation is adopted.