INTRODUCTION: Maternal diabetes is a recognized risk factor for both short-term and long-term complications in offspring. Beyond the direct teratogenicity of maternal diabetes, the intrauterine environment can influence the offspring's cardiovascular health. Abnormalities in the cardiac sympathetic system are implicated in conditions such as sudden infant death syndrome, cardiac arrhythmic death, heart failure, and certain congenital heart defects in children from diabetic pregnancies. However, the mechanisms by which maternal diabetes affects the development of the cardiac sympathetic system and, consequently, heightens health risks and predisposes to cardiovascular disease remain poorly understood. METHODS AND RESULTS: In the mouse model, we performed a comprehensive analysis of the combined impact of a Hif1a-deficient sympathetic system and the maternal diabetes environment on both heart development and the formation of the cardiac sympathetic system. The synergic negative effect of exposure to maternal diabetes and Hif1a deficiency resulted in the most pronounced deficit in cardiac sympathetic innervation and the development of the adrenal medulla. Abnormalities in the cardiac sympathetic system were accompanied by a smaller heart, reduced ventricular wall thickness, and dilated subepicardial veins and coronary arteries in the myocardium, along with anomalies in the branching and connections of the main coronary arteries. Transcriptional profiling by RNA sequencing (RNA-seq) revealed significant transcriptome changes in Hif1a-deficient sympathetic neurons, primarily associated with cell cycle regulation, proliferation, and mitosis, explaining the shrinkage of the sympathetic neuron population. DISCUSSION: Our data demonstrate that a failure to adequately activate the HIF-1α regulatory pathway, particularly in the context of maternal diabetes, may contribute to abnormalities in the cardiac sympathetic system. In conclusion, our findings indicate that the interplay between deficiencies in the cardiac sympathetic system and subtle structural alternations in the vasculature, microvasculature, and myocardium during heart development not only increases the risk of cardiovascular disease but also diminishes the adaptability to the stress associated with the transition to extrauterine life, thus increasing the risk of neonatal death.

• Klíčová slova
• cardiac sympathetic system, coronary arteries, maternal diabetes, mouse model, sympathetic neurons,
• MeSH
• dítě MeSH
• faktor 1 indukovatelný hypoxií - podjednotka alfa metabolismus   MeSH
• gestační diabetes * metabolismus   MeSH
• kardiovaskulární nemoci * metabolismus   MeSH
• lidé MeSH
• myokard metabolismus   MeSH
• myši MeSH
• novorozenec MeSH
• srdce MeSH
• srdeční selhání * MeSH
• těhotenství MeSH
• zvířata MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• myši MeSH
• novorozenec MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• faktor 1 indukovatelný hypoxií - podjednotka alfa MeSH
• Hif1a protein, mouse MeSH Prohlížeč

BACKGROUND: An altered sympathetic nervous system is implicated in many cardiac pathologies, ranging from sudden infant death syndrome to common diseases of adulthood such as hypertension, myocardial ischemia, cardiac arrhythmias, myocardial infarction, and heart failure. Although the mechanisms responsible for disruption of this well-organized system are the subject of intensive investigations, the exact processes controlling the cardiac sympathetic nervous system are still not fully understood. A conditional knockout of the Hif1a gene was reported to affect the development of sympathetic ganglia and sympathetic innervation of the heart. This study characterized how the combination of HIF-1α deficiency and streptozotocin (STZ)-induced diabetes affects the cardiac sympathetic nervous system and heart function of adult animals. METHODS: Molecular characteristics of Hif1a deficient sympathetic neurons were identified by RNA sequencing. Diabetes was induced in Hif1a knockout and control mice by low doses of STZ treatment. Heart function was assessed by echocardiography. Mechanisms involved in adverse structural remodeling of the myocardium, i.e. advanced glycation end products, fibrosis, cell death, and inflammation, was assessed by immunohistological analyses. RESULTS: We demonstrated that the deletion of Hif1a alters the transcriptome of sympathetic neurons, and that diabetic mice with the Hif1a-deficient sympathetic system have significant systolic dysfunction, worsened cardiac sympathetic innervation, and structural remodeling of the myocardium. CONCLUSIONS: We provide evidence that the combination of diabetes and the Hif1a deficient sympathetic nervous system results in compromised cardiac performance and accelerated adverse myocardial remodeling, associated with the progression of diabetic cardiomyopathy.

• Klíčová slova
• Cardiac function, Collagen deposition, Diabetic cardiomyopathy, Inflammation, Sympathetic neurons,
• MeSH
• diabetická kardiomyopatie * genetika   MeSH
• experimentální diabetes mellitus * chemicky indukované   genetika   komplikace   MeSH
• myokard metabolismus   MeSH
• myši MeSH
• srdce inervace   MeSH
• sympatický nervový systém metabolismus   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• Hif1a protein, mouse MeSH Prohlížeč

The heart is able to metabolize any substrate, depending on its availability, to satisfy its energy requirements. Under normal physiological conditions, about 95% of ATP is produced by oxidative phosphorylation and the rest by glycolysis. Cardiac metabolism undergoes reprograming in response to a variety of physiological and pathophysiological conditions. Hypoxia-inducible factor 1 (HIF-1) mediates the metabolic adaptation to hypoxia and ischemia, including the transition from oxidative to glycolytic metabolism. During embryonic development, HIF-1 protects the embryo from intrauterine hypoxia, its deletion as well as its forced expression are embryonically lethal. A decrease in HIF-1 activity is crucial during perinatal remodeling when the heart switches from anaerobic to aerobic metabolism. In the adult heart, HIF-1 protects against hypoxia, although its deletion in cardiomyocytes affects heart function even under normoxic conditions. Diabetes impairs HIF-1 activation and thus, compromises HIF-1 mediated responses under oxygen-limited conditions. Compromised HIF-1 signaling may contribute to the teratogenicity of maternal diabetes and diabetic cardiomyopathy in adults. In this review, we discuss the function of HIF-1 in the heart throughout development into adulthood, as well as the deregulation of HIF-1 signaling in diabetes and its effects on the embryonic and adult heart.

• Klíčová slova
• cardiomyopathy, embryopathy, fetal programing, heart development, hypoxia-inducible factor 1,
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

BACKGROUND: Hypoxia inducible factor 1 (HIF-1) activates protective pathways to counteract hypoxia and prevent tissue damage in conjunction with renal injury. The aim of this study was to evaluate a role of HIF-1 in diabetes-induced kidney damage. METHODS: We used a streptozotocin-induced diabetes mouse model and compared biochemical, histological and molecular parameters associated with kidney damage in Hif1α deficient (Hif1α +/- ) and wild-type mice. RESULTS: We showed that Hif1α deficiency accelerated pathological changes in the early stage of DN. Six weeks after diabetes-induction, Hif1α deficient mice showed more prominent changes in biochemical serum parameters associated with glomerular injury, increased expression of podocyte damage markers, and loss of podocytes compared to wild-type mice. These results indicate that Hif1α deficiency specifically affects podocyte survival in the early phase of DN, resulting in diabetic glomerular injury. In contrast, renal fibrosis was not affected by the global reduction of Hif1α, at least not in the early phase of diabetic exposure. CONCLUSIONS: Together our data reveal that HIF-1 has an essential role in the early response to prevent diabetes-induced tissue damage and that impaired HIF-1 signaling results in a faster progression of DN. Although the modulation of HIF-1 activity is a high-priority target for clinical treatments, further study is required to investigate HIF-1 as a potential therapeutic target for the treatment of DN.

• Klíčová slova
• Diabetic complications, Diabetic nephropathy, Hypoxia, Mouse model, Podocyte,
• MeSH
• diabetické nefropatie etiologie   metabolismus   patologie   MeSH
• experimentální diabetes mellitus komplikace   patofyziologie   MeSH
• faktor 1 indukovatelný hypoxií - podjednotka alfa nedostatek   genetika   MeSH
• modely nemocí na zvířatech * MeSH
• myši MeSH
• prognóza MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• faktor 1 indukovatelný hypoxií - podjednotka alfa MeSH
• Hif1a protein, mouse MeSH Prohlížeč