Hypoxia Sensing of ß-Adrenergic Receptor Is Regulated by Endosomal PI3Kγ.

BACKGROUND: Impaired beta-adrenergic receptor (ß1 and ß2AR) function following hypoxia underlies ischemic heart failure/stroke. Activation of PI3Kγ (phosphoinositide 3-kinase γ) by beta-adrenergic receptor leads to feedback regulation of the receptor by hindering beta-adrenergic receptor dephosphorylation through inhibition of PP2A (protein phosphatase 2A). However, little is known about PI3Kγ feedback mechanism in regulating hypoxia-mediated ß1 and ß2AR dysfunction and cardiac remodeling. METHODS: Human embryonic kidney 293 cells or mouse adult cardiomyocytes and C57BL/6 (WT) or PI3Kγ knockout (KO) mice were subjected to hypoxia. Cardiac plasma membranes and endosomes were isolated and evaluated for ß1 and ß2AR density and function, PI3Kγ activity and ß1 and ß2AR-associated PP2A activity. Metabolic labeling was performed to assess ß1 and ß2AR phosphorylation and epinephrine/norepinephrine levels measured post-hypoxia. RESULTS: Hypoxia increased ß1 and ß2AR phosphorylation, reduced cAMP, and led to endosomal accumulation of phosphorylated ß2ARs in human embryonic kidney 293 cells and WT cardiomyocytes. Acute hypoxia in WT mice resulted in cardiac remodeling and loss of adenylyl cyclase activity associated with increased ß1 and ß2AR phosphorylation. This was agonist-independent as plasma and cardiac epinephrine and norepinephrine levels were unaltered. Unexpectedly, PI3Kγ activity was selectively increased in the endosomes of human embryonic kidney 293 cells and WT hearts post-hypoxia. Endosomal ß1- and ß2AR-associated PP2A activity was inhibited upon hypoxia in human embryonic kidney 293 cells and WT hearts showing regulation of beta-adrenergic receptors by PI3Kγ. This was accompanied with phosphorylation of endogenous inhibitor of protein phosphatase 2A whose phosphorylation by PI3Kγ inhibits PP2A. Increased ß1 and ß2AR-associated PP2A activity, decreased beta-adrenergic receptor phosphorylation, and normalized cardiac function was observed in PI3Kγ KO mice despite hypoxia. Compared to WT, PI3Kγ KO mice had preserved cardiac response to challenge with ß1AR-selective agonist dobutamine post-hypoxia. CONCLUSIONS: Agonist-independent activation of PI3Kγ underlies hypoxia sensing as its ablation leads to reduction in ß1- and ß2AR phosphorylation and amelioration of cardiac dysfunction.

Preliminary outcome of Nellix-in-Nellix extensions in patients treated with failed endovascular aneurysm sealing.

BACKGROUND: The 1-year results of the use of the Nellix (Endologix Inc, Irvine, Calif) endovascular aneurysm sealing (EVAS) device were initially promising. However, midterm complications including migration and aneurysm growth occurred more frequently than expected, which provided an incentive to refine the instructions for use. Strategies for the management of complications arising after endovascular aneurysm repair are often not applicable for EVAS, given the unique configuration of the Nellix device, and new techniques are needed. This study analyzes the clinical outcomes of both elective and emergency deployment of a new Nellix device within a primarily placed device, for failure of EVAS, which we refer to as a Nellix-in-Nellix application (NINA). METHODS: This is a global, retrospective, observational cohort study focusing on the early outcome of NINA for failed EVAS, including data from 11 European institutions and 1 hospital in New Zealand. RESULTS: A total of 41 patients were identified who underwent a NINA procedure. Of these, 32 (78%) were placed electively and 9 (22%) were placed on an emergency basis. Seven patients were initially treated with chimney EVAS (n = 5 in the elective NINA group and n = 2 in the emergency NINA group). The average time between the primary EVAS procedure and NINA was 573 days (interquartile range, [IQR] 397-1078 days) and 478 days (IQR, 120-806) for the elective and emergency groups, respectively. The indication for elective NINA was endoleak with migration (50%), endoleak without migration (25%), migration without endoleak (16%), and other (9%). Chimney grafts were used in 21 of 32 patients in the elective group and 3 of 9 patients in the emergency group. Technical success was achieved in 94% of patients in the elective group and 100% of patients in the emergency group. At latest follow-up (median, 104 days; IQR, 49-328 days), there were three aneurysm-related deaths (9%), no ruptures, and five device-related reinterventions (16%) within the elective group. In the emergency group (median follow-up, 23 days; IQR, 7-61 days), there were four aneurysm-related deaths and three aneurysm-related reinterventions. CONCLUSIONS: In conclusion, a NINA can be used to treat late failures of EVAS with an acceptable technical success rate and can be used when more established treatment options are unfeasible or contraindicated. The durability of this technique needs to be further reviewed.

Editor's Choice - The Implications of Non-compliance to Endovascular Aneurysm Repair Surveillance: A Systematic Review and Meta-analysis.

OBJECTIVE/BACKGROUND: Increasingly, reports show that compliance rates with endovascular aneurysm repair (EVAR) surveillance are often suboptimal. The aim of this study was to determine the safety implications of non-compliance with surveillance. METHODS: The study was carried out according to the Preferred Items for Reporting of Systematic Reviews and Meta-Analyses (PRISMA) guidelines. An electronic search was undertaken by two independent authors using Embase, MEDLINE, Cochrane, and Web of Science databases from 1990 to July 2017. Only studies that analysed infrarenal EVAR and had a definition of non-compliance described as weeks or months without imaging surveillance were analysed. Meta-analysis was carried out using the random-effects model and restricted maximum likelihood estimation. RESULTS: Thirteen articles (40,730 patients) were eligible for systematic review; of these, seven studies (14,311 patients) were appropriate for comparative meta-analyses of mortality rates. Three studies (8316 patients) were eligible for the comparative meta-analyses of re-intervention rates after EVAR and four studies (12,995 patients) eligible for meta-analysis for abdominal aortic aneurysm related mortality (ARM). The estimated average non-compliance rate was 42.0% (95% confidence interval [CI] 28-56%). Although there is some evidence that non-compliant patients have better survival rates, there was no statistically significant difference in all cause mortality rates (year 1: odds ratio [OR] 5.77, 95% CI 0.74-45.14; year 3: OR 2.28, 95% CI 0.92-5.66; year 5: OR 1.81, 95% CI 0.88-3.74) and ARM (OR 1.47, 95% CI 0.99-2.19) between compliant and non-compliant patients in the first 5 years after EVAR. The re-intervention rate was statistically significantly higher in compliant patients from 3 to 5 years after EVAR (year 1: OR 6.36, 95% CI 0.23-172.73; year 3: OR 3.94, 85% CI 1.46-10.69; year 5: OR 5.34, 95% CI 1.87-15.29). CONCLUSION: This systematic review and meta-analysis suggests that patients compliant with EVAR surveillance programmes may have an increased re-intervention rate but do not appear to have better survival rates than non-compliant patients.

Gut microbe-generated phenylacetylglutamine is an endogenous allosteric modulator of ß2-adrenergic receptors.

Allosteric modulation is a central mechanism for metabolic regulation but has yet to be described for a gut microbiota-host interaction. Phenylacetylglutamine (PAGln), a gut microbiota-derived metabolite, has previously been clinically associated with and mechanistically linked to cardiovascular disease (CVD) and heart failure (HF). Here, using cells expressing ß1- versus ß2-adrenergic receptors (ß1AR and ß2AR), PAGln is shown to act as a negative allosteric modulator (NAM) of ß2AR, but not ß1AR. In functional studies, PAGln is further shown to promote NAM effects in both isolated male mouse cardiomyocytes and failing human heart left ventricle muscle (contracting trabeculae). Finally, using in silico docking studies coupled with site-directed mutagenesis and functional analyses, we identified sites on ß2AR (residues E122 and V206) that when mutated still confer responsiveness to canonical ß2AR agonists but no longer show PAGln-elicited NAM activity. The present studies reveal the gut microbiota-obligate metabolite PAGln as an endogenous NAM of a host GPCR.

Cardiac expression of microRNA-7 is associated with adverse cardiac remodeling.

Although microRNA-7 (miRNA-7) is known to regulate proliferation of cancer cells by targeting Epidermal growth factor receptor (EGFR/ERBB) family, less is known about its role in cardiac physiology. Transgenic (Tg) mouse with cardiomyocyte-specific overexpression of miRNA-7 was generated to determine its role in cardiac physiology and pathology. Echocardiography on the miRNA-7 Tg mice showed cardiac dilation instead of age-associated physiological cardiac hypertrophy observed in non-Tg control mice. Subjecting miRNA-7 Tg mice to transverse aortic constriction (TAC) resulted in cardiac dilation associated with increased fibrosis bypassing the adaptive cardiac hypertrophic response to TAC. miRNA-7 expression in cardiomyocytes resulted in significant loss of ERBB2 expression with no changes in ERBB1 (EGFR). Cardiac proteomics in the miRNA-7 Tg mice showed significant reduction in mitochondrial membrane structural proteins compared to NTg reflecting role of miRNA-7 beyond the regulation of EGFR/ERRB in mediating cardiac dilation. Consistently, electron microscopy showed that miRNA-7 Tg hearts had disorganized rounded mitochondria that was associated with mitochondrial dysfunction. These findings show that expression of miRNA-7 in the cardiomyocytes results in cardiac dilation instead of adaptive hypertrophic response during aging or to TAC providing insights on yet to be understood role of miRNA-7 in cardiac function.