| 1. |
- Vantler, Marius, et al.
(författare)
-
Class IA Phosphatidylinositol 3-Kinase Isoform p110 alpha Mediates Vascular Remodeling
- 2015
-
Ingår i: Arteriosclerosis, Thrombosis and Vascular Biology. - 1079-5642 .- 1524-4636. ; 35:6, s. 1434-1444
-
Tidskriftsartikel (refereegranskat)abstract
- Objective-Neointima formation after vascular injury remains a significant problem in clinical cardiology, and current preventive strategies are suboptimal. Phosphatidylinositol 3'-kinase is a central downstream mediator of growth factor signaling, but the role of phosphatidylinositol 3'-kinase isoforms in vascular remodeling remains elusive. We sought to systematically characterize the precise role of catalytic class IA phosphatidylinositol 3'-kinase isoforms (p110 alpha, p110 beta, p110 delta), which signal downstream of receptor tyrosine kinases, for vascular remodeling in vivo. Approach and Results-Western blot analyses revealed that all 3 isoforms are abundantly expressed in smooth muscle cells. To analyze their significance for receptor tyrosine kinases-dependent cellular responses, we used targeted gene knockdown and isoform-specific small molecule inhibitors of p110 alpha (PIK-75), p110 beta (TGX-221), and p110 delta (IC-87114), respectively. We identified p110 alpha to be crucial for receptor tyrosine kinases signaling, thus affecting proliferation, migration, and survival of rat, murine, and human smooth muscle cells, whereas p110 beta and p110 delta activities were dispensable. Surprisingly, p110 delta exerted noncatalytic functions in smooth muscle cell proliferation, but had no effect on migration. Based on these results, we generated a mouse model of smooth muscle cell-specific p110 alpha deficiency (sm-p110 alpha(-/-)). Targeted deletion of p110 alpha in sm-p110 alpha(-/-) mice blunted growth factor-induced cellular responses and abolished neointima formation after balloon injury of the carotid artery in mice. In contrast, p110 delta deficiency did not affect vascular remodeling in vivo. Conclusions-Receptor tyrosine kinases-induced phosphatidylinositol 3'-kinase signaling via the p110 alpha isoform plays a central role for vascular remodeling in vivo. Thus, p110 alpha represents a selective target for the prevention of neointima formation after vascular injury, whereas p110 beta and p110 delta expression and activity do not play a significant role.
|
|
| 2. |
- Aktaa, Suleman, et al.
(författare)
-
European Society of Cardiology quality indicators for the care and outcomes of adults with pulmonary arterial hypertension. Developed in collaboration with the Heart Failure Association of the European Society of Cardiology
- 2023
-
Ingår i: European Journal of Heart Failure. - : Wiley. - 1388-9842 .- 1879-0844. ; 25:4, s. 469-477
-
Tidskriftsartikel (refereegranskat)abstract
- Aims: To develop a suite of quality indicators (QIs) for the evaluation of the care and outcomes for adults with pulmonary arterial hypertension (PAH). Methods and results: We followed the European Society of Cardiology (ESC) methodology for the development of QIs. This included (i) the identification of key domains of care for the management of PAH, (ii) the proposal of candidate QIs following systematic review of the literature, and (iii) the selection of a set of QIs using a modified Delphi method. The process was undertaken in parallel with the writing of the 2022 ESC/European Respiratory Society (ERS) guidelines for the diagnosis and treatment of pulmonary hypertension and involved the Task Force chairs, experts in PAH, Heart Failure Association (HFA) members and patient representatives. We identified five domains of care for patients with PAH: structural framework, diagnosis and risk stratification, initial treatment, follow-up, and outcomes. In total, 23 main and one secondary QIs for PAH were selected. Conclusion: This document presents the ESC QIs for PAH, describes their development process and offers scientific rationale for their selection. The indicators may be used to quantify and improve adherence to guideline-recommended clinical practice and improve patient outcomes.
|
|
| 3. |
- Caglayan, Evren, et al.
(författare)
-
Disruption of Platelet-Derived Growth Factor-Dependent Phosphatidylinositol 3-Kinase and Phospholipase C gamma 1 Activity Abolishes Vascular Smooth Muscle Cell Proliferation and Migration and Attenuates Neointima Formation In Vivo
- 2011
-
Ingår i: Journal of the American College of Cardiology. - : Elsevier BV. - 0735-1097 .- 1558-3597. ; 57:25, s. 2527-2538
-
Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: We tested the hypothesis whether selective blunting of platelet-derived growth factor (PDGF)-dependent vascular smooth muscle cell (VSMC) proliferation and migration is sufficient to prevent neointima formation after vascular injury. BACKGROUND: To prevent neointima formation and stent thrombosis after coronary interventions, it is essential to inhibit VSMC proliferation and migration without harming endothelial cell function. The role of PDGF-a potent mitogen and chemoattractant for VSMC that does not affect endothelial cells-for neointima formation remains controversial. METHODS: To decipher the signaling pathways that control PDGF beta receptor (βPDGFR)-driven VSMC proliferation and migration, we characterized 2 panels of chimeric CSF1R/βPDGFR mutants in which the binding sites for βPDGFR-associated signaling molecules (Src, phosphatidylinositol 3-kinase [PI3K], GTPase activating protein of ras, SHP-2, phospholipase Cγ 1 [PLCγ]) were individually mutated. Based on in vitro results, the importance of PDGF-initiated signals for neointima formation was investigated in genetically modified mice. RESULTS: Our results indicate that the chemotactic response to PDGF requires the activation of Src, PI3K, and PLCγ, whereas PDGF-dependent cell cycle progression is exclusively mediated by PI3K and PLCγ. These 2 signaling molecules contribute to signal relay of the βPDGFR by differentially regulating cyclin D1 and p27(kip1). Blunting of βPDGFR-induced PI3K and PLCγ signaling by a combination mutant (F3) completely abolished the mitogenic and chemotactic response to PDGF. Disruption of PDGF-dependent PI3K and PLCγ signaling in mice expressing the F3 receptor led to a profound reduction of neointima formation after balloon injury. CONCLUSIONS: Signaling by the activated βPDGFR, particularly through PI3K and PLCγ, is crucial for neointima formation after vascular injury. Disruption of these specific signaling pathways is sufficient to attenuate pathogenic processes such as vascular remodeling in vivo.
|
|
| 4. |
- Gorski, Mathias, et al.
(författare)
-
Genetic loci and prioritization of genes for kidney function decline derived from a meta-analysis of 62 longitudinal genome-wide association studies
- 2022
-
Ingår i: Kidney International. - : Elsevier. - 0085-2538 .- 1523-1755. ; 102:3, s. 624-639
-
Tidskriftsartikel (refereegranskat)abstract
- Estimated glomerular filtration rate (eGFR) reflects kidney function. Progressive eGFR-decline can lead to kidney failure, necessitating dialysis or transplantation. Hundreds of loci from genome-wide association studies (GWAS) for eGFR help explain population cross section variability. Since the contribution of these or other loci to eGFR-decline remains largely unknown, we derived GWAS for annual eGFR-decline and meta-analyzed 62 longitudinal studies with eGFR assessed twice over time in all 343,339 individuals and in high-risk groups. We also explored different covariate adjustment. Twelve genomewide significant independent variants for eGFR-decline unadjusted or adjusted for eGFR- baseline (11 novel, one known for this phenotype), including nine variants robustly associated across models were identified. All loci for eGFR-decline were known for cross-sectional eGFR and thus distinguished a subgroup of eGFR loci. Seven of the nine variants showed variant- by-age interaction on eGFR cross section (further about 350,000 individuals), which linked genetic associations for eGFR-decline with agedependency of genetic cross- section associations. Clinically important were two to four-fold greater genetic effects on eGFR-decline in high-risk subgroups. Five variants associated also with chronic kidney disease progression mapped to genes with functional in- silico evidence (UMOD, SPATA7, GALNTL5, TPPP). An unfavorable versus favorable nine-variant genetic profile showed increased risk odds ratios of 1.35 for kidney failure (95% confidence intervals 1.03- 1.77) and 1.27 for acute kidney injury (95% confidence intervals 1.08-1.50) in over 2000 cases each, with matched controls). Thus, we provide a large data resource, genetic loci, and prioritized genes for kidney function decline, which help inform drug development pipelines revealing important insights into the age-dependency of kidney function genetics.
|
|
| 5. |
- Gorski, Mathias, et al.
(författare)
-
Meta-analysis uncovers genome-wide significant variants for rapid kidney function decline
- 2021
-
Ingår i: Kidney International. - : Elsevier. - 0085-2538 .- 1523-1755. ; 99:4, s. 926-939
-
Tidskriftsartikel (refereegranskat)abstract
- Rapid decline of glomerular filtration rate estimated from creatinine (eGFRcrea) is associated with severe clinical endpoints. In contrast to cross-sectionally assessed eGFRcrea, the genetic basis for rapid eGFRcrea decline is largely unknown. To help define this, we meta-analyzed 42 genome-wide association studies from the Chronic Kidney Diseases Genetics Consortium and United Kingdom Biobank to identify genetic loci for rapid eGFRcrea decline. Two definitions of eGFRcrea decline were used: 3 mL/min/1.73m2/year or more ("Rapid3"; encompassing 34,874 cases, 107,090 controls) and eGFRcrea decline 25% or more and eGFRcrea under 60 mL/min/1.73m2 at follow-up among those with eGFRcrea 60 mL/min/1.73m2 or more at baseline ("CKDi25"; encompassing 19,901 cases, 175,244 controls). Seven independent variants were identified across six loci for Rapid3 and/or CKDi25: consisting of five variants at four loci with genome-wide significance (near UMOD-PDILT (2), PRKAG2, WDR72, OR2S2) and two variants among 265 known eGFRcrea variants (near GATM, LARP4B). All these loci were novel for Rapid3 and/or CKDi25 and our bioinformatic follow-up prioritized variants and genes underneath these loci. The OR2S2 locus is novel for any eGFRcrea trait including interesting candidates. For the five genome-wide significant lead variants, we found supporting effects for annual change in blood urea nitrogen or cystatin-based eGFR, but not for GATM or LARP4B. Individuals at high compared to those at low genetic risk (8-14 vs 0-5 adverse alleles) had a 1.20-fold increased risk of acute kidney injury (95% confidence interval 1.08-1.33). Thus, our identified loci for rapid kidney function decline may help prioritize therapeutic targets and identify mechanisms and individuals at risk for sustained deterioration of kidney function.
|
|
| 6. |
|
|
| 7. |
- Kappert, Kai, et al.
(författare)
-
Antioxidants relieve phosphatase inhibition and reduce PDGF signaling in cultured VSMCs and in restenosis
- 2006
-
Ingår i: Arteriosclerosis, Thrombosis and Vascular Biology. - 1079-5642 .- 1524-4636. ; 26:12, s. 2644-2651
-
Tidskriftsartikel (refereegranskat)abstract
- Objective - Growth factor- and reactive oxygen species (ROS)-induced activation of VSMCs is involved in vascular disease. This study investigates whether inhibitory oxidation of protein tyrosine phosphatases (PTPs) contributes to signaling in VSMCs in vitro and in vivo, and analyzes whether ROS- and growth factor-dependent vascular smooth muscle cell (VSMC) signaling is blunted by antioxidants that are able to activate oxidized PTPs. Methods and Results - Signaling induced by H2O2 and platelet-derived growth factor (PDGF) was analyzed in VSMCs with or without the antioxidants N-acetyl-cysteine (NAC) and tempol. Effects of antioxidants on PDGF-stimulated chemotaxis and proliferation were determined. In vivo effects of antioxidants were analyzed in the rat carotid balloon-injury model, by analyzing neointima formation, cell proliferation, PDGF beta-receptor status, and PTP expression and activity. NAC treatment prevented H2O2-induced PTP inhibition, and reduced H2O2-and ligand-induced PDGF beta-receptor phosphorylation, PDGF-induced proliferation, and chemotaxis of VSMCs. Antioxidants inhibited neointima formation and reduced PDGF receptor phosphorylation in the neointima and also increased PTP activity. Conclusion - PTP-inhibition was identified as an intrinsic component of H2O2-and PDGF-induced signaling in cultured VSMCs. The reduction in PDGF beta-receptor phosphorylation in vivo, and the increase in PTP activity, by antioxidants indicate activation of oxidized PTPs as a previously unrecognized mechanism for the antirestenotic effects of antioxidants. The findings thus suggest, in general terms, reactivation of oxidized PTPs as a novel antirestenotic strategy.
|
|
| 8. |
- Kappert, Kai, et al.
(författare)
-
Highly Active Antiretroviral Therapy Attenuates Re-Endothelialization and Alters Neointima Formation in the Rat Carotid Artery After Balloon Injury
- 2006
-
Ingår i: Journal of Acquired Immune Deficiency Syndromes. - : Ovid Technologies (Wolters Kluwer Health). - 1525-4135 .- 1944-7884. ; 43:4, s. 383-392
-
Tidskriftsartikel (refereegranskat)abstract
- Highly active antiretroviral therapy (HAART) has led to a sustained decline of HIV-associated morbidity and mortality. HAART exhibits significant side effects, however, such as hyperlipidemia and hyperglycemia, which possibly contribute to accelerated atherosclerosis in HAART-treated patients. In addition, direct effects of HAART on vascular cells have been described, which may promote atherosclerotic lesion formation. The effects of HAART on balloon-induced neointima formation have not been studied previously. The rat carotid artery balloon model was used to evaluate the effects of HAART (lopinavir, ritonavir, lamivudine, and zidovudine) on neointima formation and endothelial recovery. Furthermore, the effects of concomitant administration of the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor rosuvastatin were investigated. HAART-treated animals displayed an increase in lesion size (neointima/media ratio: 1.14 +/- 0.32 vs. 1.31 +/- 0.20 in control vs. HAART; P < 0.05) and an impaired regenerative capacity of the endothelium, as indicated by reduction in endothelial regrowth from an adjacent undilated vessel segment 14 days after injury (re-endothelialization area: 8.29 +/- 1.45 mm vs. 5.09 +/- 0.53 mm in control vs. HAART; P < 0.05). When rosuvastatin was given in addition to HAART, these effects were not observed. In conclusion, HAART inhibited endothelial cell-mediated healing and promoted neointima formation after angioplasty in rats. These deleterious effects were attenuated by cotreatment with rosuvastatin, however. Our studies suggest that currently used drug regimens against HIV infection may lead to an increased risk for restenosis after percutaneous vascular interventions. Moreover, the findings indicate that the additional treatment with statins might counteract these adverse effects by HAART.
|
|
| 9. |
|
|
