Hypertrophic cardiomyopathy (HCM) caused by autosomal-dominant mutations in genes coding for structural sarcomeric proteins, is the most common inherited heart disease. HCM is associated with myocardial hypertrophy, fibrosis and ventricular dysfunction. Hypoxia-inducible transcription factor-1α (Hif-1α) is the central master regulators of cellular hypoxia response and associated with HCM. Yet its exact role remains to be elucidated. Therefore, the effect of a cardiomyocyte-specific Hif-1a knockout (cHif1aKO) was studied in an established α-MHC719/+ HCM mouse model that exhibits the classical features of human HCM. The results show that Hif-1α protein and HIF targets were upregulated in left ventricular tissue of α-MHC719/+ mice. Cardiomyocyte-specific abolishment of Hif-1a blunted the disease phenotype, as evidenced by decreased left ventricular wall thickness, reduced myocardial fibrosis, disordered SRX/DRX state and ROS production. cHif1aKO induced normalization of pro-hypertrophic and pro-fibrotic left ventricular remodeling signaling evidenced on whole transcriptome and proteomics analysis in α-MHC719/+ mice. Proteomics of serum samples from patients with early onset HCM revealed significant modulation of HIF. These results demonstrate that HIF signaling is involved in mouse and human HCM pathogenesis. Cardiomyocyte-specific knockout of Hif-1a attenuates disease phenotype in the mouse model. Targeting Hif-1α might serve as a therapeutic option to mitigate HCM disease progression.
- Klíčová slova
- HIF1A, Hypertrophic cardiomyopathy, Hypertrophy, Hypoxia, Myocardial fibrosis,
- MeSH
- faktor 1 indukovatelný hypoxií - podjednotka alfa * metabolismus genetika MeSH
- fibróza MeSH
- hypertrofická kardiomyopatie * metabolismus genetika patologie MeSH
- kardiomyocyty * metabolismus patologie MeSH
- lidé MeSH
- modely nemocí na zvířatech * MeSH
- myši knockoutované * MeSH
- myši MeSH
- sarkomery * metabolismus MeSH
- signální transdukce MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- faktor 1 indukovatelný hypoxií - podjednotka alfa * MeSH
- Hif1a protein, mouse MeSH Prohlížeč
Clinical presentation of congenital heart disease is heterogeneous, making identification of the disease-causing genes and their genetic pathways and mechanisms of action challenging. By using in vivo electrocardiography, transthoracic echocardiography and microcomputed tomography imaging to screen 3,894 single-gene-null mouse lines for structural and functional cardiac abnormalities, here we identify 705 lines with cardiac arrhythmia, myocardial hypertrophy and/or ventricular dilation. Among these 705 genes, 486 have not been previously associated with cardiac dysfunction in humans, and some of them represent variants of unknown relevance (VUR). Mice with mutations in Casz1, Dnajc18, Pde4dip, Rnf38 or Tmem161b genes show developmental cardiac structural abnormalities, with their human orthologs being categorized as VUR. Using UK Biobank data, we validate the importance of the DNAJC18 gene for cardiac homeostasis by showing that its loss of function is associated with altered left ventricular systolic function. Our results identify hundreds of previously unappreciated genes with potential function in congenital heart disease and suggest causal function of five VUR in congenital heart disease.
- Publikační typ
- časopisecké články MeSH
Cardiovascular side effects are frequent problems accompanying systemic glucocorticoid therapy, although the underlying mechanisms are not fully resolved. Reactive oxygen species (ROS) have been shown to promote various cardiovascular diseases although the link between glucocorticoid and ROS signaling has been controversial. As the family of NADPH oxidases has been identified as important source of ROS in the cardiovascular system we investigated the role of NADPH oxidases in response to the synthetic glucocorticoid dexamethasone in the cardiovascular system in vitro and in vivo in mice lacking functional NADPH oxidases due to a mutation in the gene coding for the essential NADPH oxidase subunit p22phox. We show that dexamethasone induced NADPH oxidase-dependent ROS generation, leading to vascular proliferation and angiogenesis due to activation of the transcription factor hypoxia-inducible factor-1 (HIF1). Chronic treatment of mice with low doses of dexamethasone resulted in the development of systemic hypertension, cardiac hypertrophy and left ventricular dysfunction, as well as in pulmonary hypertension and pulmonary vascular remodeling. In contrast, mice deficient in p22phox-dependent NADPH oxidases were protected against these cardiovascular side effects. Mechanistically, dexamethasone failed to upregulate HIF1α levels in these mice, while vascular HIF1α deficiency prevented pulmonary vascular remodeling. Thus, p22phox-dependent NADPH oxidases and activation of the HIF pathway are critical elements in dexamethasone-induced cardiovascular pathologies and might provide interesting targets to limit cardiovascular side effects in patients on chronic glucocorticoid therapy.
- Klíčová slova
- Glucocorticoid, HIF1, Hypertension, NADPH oxidase, Pulmonary vascular remodeling, ROS, p22phox,
- MeSH
- faktor 1 indukovatelný hypoxií MeSH
- glukokortikoidy MeSH
- lidé MeSH
- myši MeSH
- NADPH-oxidasy genetika MeSH
- nemoci srdce * MeSH
- plicní hypertenze * chemicky indukované MeSH
- reaktivní formy kyslíku MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- faktor 1 indukovatelný hypoxií MeSH
- glukokortikoidy MeSH
- NADPH-oxidasy MeSH
- reaktivní formy kyslíku MeSH
The molecular mechanisms regulating sympathetic innervation of the heart during embryogenesis and its importance for cardiac development and function remain to be fully elucidated. We generated mice in which conditional knockout (CKO) of the Hif1a gene encoding the transcription factor hypoxia-inducible factor 1α (HIF-1α) is mediated by an Islet1-Cre transgene expressed in the cardiac outflow tract, right ventricle and atrium, pharyngeal mesoderm, peripheral neurons, and hindlimbs. These Hif1aCKO mice demonstrate significantly decreased perinatal survival and impaired left ventricular function. The absence of HIF-1α impaired the survival and proliferation of preganglionic and postganglionic neurons of the sympathetic system, respectively. These defects resulted in hypoplasia of the sympathetic ganglion chain and decreased sympathetic innervation of the Hif1aCKO heart, which was associated with decreased cardiac contractility. The number of chromaffin cells in the adrenal medulla was also decreased, indicating a broad dependence on HIF-1α for development of the sympathetic nervous system.
- Klíčová slova
- cardiac innervation, coronary artery branching, hypoxia, sympathetic neurons, tyrosine hydroxylase,
- MeSH
- anomálie koronárních cév embryologie MeSH
- chromafinní buňky MeSH
- dřeň nadledvin embryologie inervace MeSH
- faktor 1 indukovatelný hypoxií - podjednotka alfa fyziologie MeSH
- koronární cévy embryologie MeSH
- myši knockoutované MeSH
- myši transgenní MeSH
- myši MeSH
- srdce embryologie inervace MeSH
- sympatická ganglia embryologie růst a vývoj MeSH
- sympatický nervový systém enzymologie růst a vývoj MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- faktor 1 indukovatelný hypoxií - podjednotka alfa MeSH
- Hif1a protein, mouse MeSH Prohlížeč
The European Cooperation in Science and Technology (COST) provides an ideal framework to establish multi-disciplinary research networks. COST Action BM1203 (EU-ROS) represents a consortium of researchers from different disciplines who are dedicated to providing new insights and tools for better understanding redox biology and medicine and, in the long run, to finding new therapeutic strategies to target dysregulated redox processes in various diseases. This report highlights the major achievements of EU-ROS as well as research updates and new perspectives arising from its members. The EU-ROS consortium comprised more than 140 active members who worked together for four years on the topics briefly described below. The formation of reactive oxygen and nitrogen species (RONS) is an established hallmark of our aerobic environment and metabolism but RONS also act as messengers via redox regulation of essential cellular processes. The fact that many diseases have been found to be associated with oxidative stress established the theory of oxidative stress as a trigger of diseases that can be corrected by antioxidant therapy. However, while experimental studies support this thesis, clinical studies still generate controversial results, due to complex pathophysiology of oxidative stress in humans. For future improvement of antioxidant therapy and better understanding of redox-associated disease progression detailed knowledge on the sources and targets of RONS formation and discrimination of their detrimental or beneficial roles is required. In order to advance this important area of biology and medicine, highly synergistic approaches combining a variety of diverse and contrasting disciplines are needed.
- Klíčová slova
- Antioxidants, Oxidative stress, Reactive nitrogen species, Reactive oxygen species, Redox signaling, Redox therapeutics,
- MeSH
- Evropská unie MeSH
- lidé MeSH
- mezinárodní spolupráce * MeSH
- molekulární biologie organizace a řízení trendy MeSH
- oxidace-redukce MeSH
- reaktivní formy kyslíku chemie metabolismus MeSH
- signální transdukce MeSH
- společnosti vědecké MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
- Názvy látek
- reaktivní formy kyslíku MeSH
