Publications

Patients with HNF1A-maturity-onset diabetes of the young (MODY) often develop endothelial dysfunction and related microvascular complications, like retinopathy. As the clinical phenotype of HNF1A-MODY diabetes varies considerably, we used human induced pluripotent stem cells (hiPSCs) from two healthy individuals (control) to generate isogenic lines with mutation in HNF1A gene. Subsequently, control hiPSCs and their respective HNF1A clones were differentiated toward endothelial cells (hiPSC-ECs) and different markers/functions were compared. Human iPSC-ECs from all cell lines showed similar expression of CD31 and Tie-2. VE-cadherin expression was lower in HNF1A-mutated isogenic lines, but only in clones derived from one control hiPSCs. In the other isogenic set and cells derived from HNF1A-MODY patients, no difference in VE-cadherin expression was observed, suggesting the impact of the genetic background on this endothelial marker. All tested hiPSC-ECs showed an expected angiogenic response regardless of the mutation introduced. Isogenic hiPSC-ECs responded similarly to stimulation with pro-inflammatory cytokine TNF-α with the increase in ICAM-1 and permeability, however, HNF1A mutated hiPSC-ECs showed higher permeability in comparison to the control cells. Summarizing, both mono- and biallelic mutations of HNF1A in hiPSC-ECs lead to increased permeability in response to TNF-α in normal glycemic conditions, which may have relevance to HNF1A-MODY microvascular complications.

It seems that interplay between HO-1 and miRNAs may be important in regulating fates of stem and progenitor cells and needs further intensive studies.

Summary: Background: Angiogenesis is a promising novel therapeutic strategy to provide new venues for blood flow in patients with severe ischaemic heart and peripheral vascular diseases. Among several stimulators, the vascular endothelial growth factor (VEGF) and fibroblast growth factor-2 (FGF-2, basic FGF) have been most widely studied. Methods: Preclinical animal studies suggested the strong therapeutic potentials of VEGF, and such positive effects have also been confirmed in a limited number of phase I clinical trials. However, some animal studies suggest the existence of a considerable risk associated with angiogenic therapy. Results: VEGF is strongly expressed in human atherosclerotic plaques, it promotes atherosclerosis in animal models, and there is evidence indicating that the plaque growth is dependent on the formation of new blood vessels. Therefore, for a convincing demonstration of the safety and efficacy of VEGF gene therapy, the clinical effects need to be evaluated in larger randomized, double-blinded clinical trials. Conclusions: Further understanding of the mechanisms of activity of angiogenic growth factors and the formation of blood vessels is required, and improved gene transfer methods are necessary to introduce therapeutic angiogenesis in clinical practice. Zusammenfassung: Grundlagen: Die Angiogenese ist eine vielversprechende neue therapeutische Strategie bei Patienten mit Myokardischämie und peripheren Gefäßerkrankungen. Unter den verschiedensten Stimulatoren sind der Vascular Endothelial Growth Factor (VEGF) und der Fibroblast Growth Factor-2 (FGF-2, basic FGF) am besten erforscht. Methodik: Vorklinische Tierversuche lassen ein großes therapeutisches Potential erwarten, und diese positiven Effekte werden von einer begrenzten Zahl von Phase-I-Studien bestätigt. Einige der experimentellen Studien lassen erhebliche Risiken in Verbindung mit einer angiogenetischen Therapie vermuten. Ergebnisse: VEGF wird von humanen atherosklerotischen Plaques verstärkt gebildet, fördert Atherosklerose am Tiermodell, und es gibt Anzeichen, daß das Plaquewachstum von der Bildung neuer Blutgefäße abhängig ist. Daher sollten die klinischen Effekte, um die Sicherheit und Effizienz einer VEGF-Gentherapie zu zeigen, in großen, randomisierten, doppelblinden, klinischen Studien evaluiert werden. Schlußfolgerungen: Um eine therapeutische Angiogenese in der klinischen Praxis anwenden zu können, ist ein genaueres Verständnis der Mechanismen der Aktivität von angiogenetischen Wachstumsfaktoren und der Bildung von Blutgefäßen und die Verbesserung der Gentransfermethoden nötig.

Hydrogen sulfide (H2S) belongs to the family of gasotransmitters and can modulate a myriad of biological signaling pathways. Among others, its cardioprotective effects, through antioxidant, anti-inflammatory, anti-fibrotic, and proangiogenic activities, are well-documented in experimental studies. Cardiorespiratory failure, predominantly cardiomyopathy, is a life-threatening complication that is the number one cause of death in patients with Duchenne muscular dystrophy (DMD). Although recent data suggest the role of H2S in ameliorating muscle wasting in murine and Caenorhabditis elegans models of DMD, possible cardioprotective effects have not yet been addressed. In this review, we summarize the current understanding of the role of H2S in animal models of cardiac dysfunctions and cardiac cells. We highlight that DMD may be amenable to H2S supplementation, and we suggest H2S as a possible factor regulating DMD-associated cardiomyopathy.