Publications

Heme oxygenase-1 (HO1) degrades heme to carbon monoxide (CO), biliverdin, and ferrous iron. Through these<br /> products, HO1 mitigates cellular injury by exerting anti-oxidant, anti-apoptotic, and anti-inflammatory effects.<br /> Several lines of evidence indicate that angiogenic factors, such as vascular endothelial growth factor A (VEGF)<br /> and stromal cell-derived factor 1 (SDF1), mediate their proangiogenic action in endothelial cells and endothelial<br /> progenitor cells through induction of HO1, and reciprocally, VEGF and SDF1 are enhanced by HO1 overexpression.<br /> Ferrous iron released during the breakdown of free heme by HO1 is an extremely pro-oxidative molecule<br /> that can be rapidly removed by ferritin. Of note, this iron sequestering protein also has been shown to exert some<br /> proangiogenic effects. Moreover, our recent data indicate that HO1 is an important mediator of differentiation<br /> and function of stem cells, including endothelial and myoblasts progenitors. All of this makes HO1 a promising<br /> target for novel cardiovascular therapies. The aim of this review is to discuss the existing knowledge and to propose<br /> the therapeutic approaches, which have to consider the necessity of tight regulation of HO1 expression.

<p>Effect of co-culture of SMS-CTR eRMS cell line and mesenchymal stromal cells (MSC) with normal HO-1 expression (MSC WT) or lacking HO-1 (MSC HO-1 KO).</p>

Heme oxygenase-1 (HO-1) is an inducible enzyme that degrades heme to carbon monoxide, iron ions, and biliverdin. Its expression can be induced by 15-deoxy-Delta(12,14)prostaglandin-J(2) (15d-PGJ(2)), a natural ligand of peroxisome proliferator-activated receptor-gamma transcription factor. In macrophages and vascular smooth muscle cells, 15d-PGJ(2) up-regulates the expression of vascular endothelial growth factor (VEGF), a fundamental regulator of angiogenesis. Here we investigated the involvement of HO-1 in the 15d-PGJ(2)-mediated regulation of VEGF production by human microvascular endothelial cells (HMEC-1). Resting HMEC-1 released approximately 20 pg/ml VEGF protein after 24 h of incubation. Treatment of cells with 15d-PGJ(2) (1-10 microM) significantly and dose-dependently increased the VEGF promoter activity, mRNA expression, and protein secretion. In the same cells, 15d-PGJ(2) potently induced the expression of HO-1 protein that correlated with HO-1 promoter activity. Activation of HO-1 with hemin or ectopic overexpression of HO-1 in HMEC-1 perfectly mimicked the effect of 15d-PGJ(2) and led to increased VEGF production. Importantly, the inhibition of the HO-1 pathway by tin protoporphyrin-IX significantly reduced the stimulatory effect of 15d-PGJ(2) on VEGF synthesis. Thus, we postulate that the up-regulation of VEGF expression in response to 15d-PGJ(2 )in HMEC-1 is mediated by the activation of HO-1.

MicroRNA-378a (miR-378a, previously known as miR-378) is one of the small noncoding RNA molecules able to regulate gene expression at posttranscriptional level. Its two mature strands, miR-378a-3p and miR-378a-5p, originate from the first intron of the peroxisome proliferator-activated receptor gamma, coactivator 1 beta ( ppargc1b ) gene encoding PGC-1 β . Embedding in the sequence of this transcriptional regulator of oxidative energy metabolism implies involvement of miR-378a in metabolic pathways, mitochondrial energy homeostasis, and related biological processes such as muscle development, differentiation, and regeneration. On the other hand, modulating the expression of proangiogenic factors such as vascular endothelial growth factor, angiopoietin-1, or interleukin-8, influencing inflammatory reaction, and affecting tumor suppressors, such as SuFu and Fus-1, miR-378a is considered as a part of an angiogenic network in tumors. In the latter, miR-378a can evoke broader actions by enhancing cell survival, reducing apoptosis, and promoting cell migration and invasion. This review describes the current knowledge on miR-378a linking oxidative/lipid metabolism, muscle biology, and blood vessel formation.

Was, H.; Tejchman, A.; Dubiel, M.; Dominik, P.; Kotlinowski, J.; Zebzda, A.; Dulak, J.; Jozkowicz, A. Author Information

Inadequate supply of oxygen (O2) is a hallmark of many diseases, in particular those related to the cardiovascular system. On the other hand, tissue hypoxia is an important factor regulating (normal) embryogenesis and differentiation of stem cells at the early stages of embryonic development. In culture, hypoxic conditions may facilitate the derivation of embryonic stem cells (ESCs) and the generation of induced pluripotent stem cells (iPSCs), which may serve as a valuable tool for disease modeling. Endothelial cells (ECs), multifunctional components of vascular structures, may be obtained from iPSCs and subsequently used in various (hypoxia-related) disease models to investigate vascular dysfunctions. Although iPSC-ECs demonstrated functionality in vitro and in vivo, ongoing studies are conducted to increase the efficiency of differentiation and to establish the most productive protocols for the application of patient-derived cells in clinics. In this review, we highlight recent discoveries on the role of hypoxia in the derivation of ESCs and the generation of iPSCs. We also summarize the existing protocols of hypoxia-driven differentiation of iPSCs toward ECs and discuss their possible applications in disease modeling and treatment of hypoxia-related disorders.

Purpose: To examine the reaction of endothelium, assess through changes of circulating blood markers of endothelial function: the stable end product of nitric oxide (NOx), dimethylarginine (ADMA), symmetric dimethylarginine (SDMA) and xanthine oxidase (XO), that promotes exercise training in patients (pts) with heart failure with preserved ejection fraction (HFpEF) vs. pts with heart failure with reduced ejection fraction (HFrEF).Methods: 62 pts after myocardial infarction: 35 with HFpEF (HFpEF group) and 27 HFrEF (HFrEF group) were studied.In all pts, before and after a short-term supervised 3 weeks exercise training at residential center values of NOx, ADMA, SDMA and XO were determined and exercise test was performed.Results: After 3 weeks of exercise training NOx increased significantly in both groups: in HFpEF group (from 33.9±6.7 to 41.7±8.5 μmol/l, P<0.0001), and in HFrEF group (from 32.5±4.3 to 39.0±7.7 μmol/l, P<0.001).Value of ADMA as well of SDMA decreased in both groups after 3 weeks: ADMA in HFpEF group from 0.360±0.07 to 0.315±0.12μmol/l (by 12.5%; P=0.059), and in HFrEF group from 0.280±0.07 to 0.264±0.06μmol/l (by 5.7%; ns); SDMA in HFpEF group from 0.290±0.09to 0.250±0.14μmol/l (by 13.7%; ns), and in HFrEF group from 0.260±0.08 to 0.230±0.05μmol/l (by 11.5%; ns).Compared to the baseline, value of XO after 3 weeks was significantly lower in both groups (P<0.0001both), however it was significantly lower in HFpEF than in HFrEF group (190.5±33.0vs 220.0±20.2μmol/l, P=0.0002).After 3 weeks exercise capacity significantly increased in HFpEF group (P<0.001), as well as in HFrEF (P<0.02)Conclusion: The way of endothelial response on exercise training, in addition to standard therapy, was equal in pts with HFpEF and in pts with HFrEF.Exercise training induced favorable modification of endothelial function, expressed through significant increased of NOx, decreased of ADMA, SDMA, and significant decreased of XO, which was more pronounced in pts withHFpEF than in pts with HFrEF.