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.

• Keywords
• cardiac sympathetic system, coronary arteries, maternal diabetes, mouse model, sympathetic neurons,
• MeSH
• Child MeSH
• Hypoxia-Inducible Factor 1, alpha Subunit metabolism   MeSH
• Diabetes, Gestational * metabolism   MeSH
• Cardiovascular Diseases * metabolism   MeSH
• Humans MeSH
• Myocardium metabolism   MeSH
• Mice MeSH
• Infant, Newborn MeSH
• Heart MeSH
• Heart Failure * MeSH
• Pregnancy MeSH
• Animals MeSH
• Check Tag
• Child MeSH
• Humans MeSH
• Mice MeSH
• Infant, Newborn MeSH
• Pregnancy MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Hypoxia-Inducible Factor 1, alpha Subunit MeSH
• Hif1a protein, mouse MeSH Browser

Cor triatriatum is a very rare cardiac malformation characterized by the presence of an abnormal interatrial membrane separating either the left or right atrial chamber into two compartments. It can be associated with other cardiac defects and is often symptomatic in childhood. The signs depend on the size and position of the interatrial membrane and other associated malformations. Here we report a case of right-sided cor triatriatum associated with an ostium primum-type interatrial septum defect and left-sided opening of the coronary sinus in a fetus. The cause of intrauterine death was asphyxia due to total placental abruption.

• Keywords
• cor triatriatum dexter, coronary artery bridging, left-sided opening of the coronary sinus, ostium primum atrioventricular septum defect,
• Publication type
• Journal Article MeSH
• Case Reports MeSH

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.

• Keywords
• Cardiac function, Collagen deposition, Diabetic cardiomyopathy, Inflammation, Sympathetic neurons,
• MeSH
• Diabetic Cardiomyopathies * genetics   MeSH
• Diabetes Mellitus, Experimental * chemically induced   genetics   complications   MeSH
• Myocardium metabolism   MeSH
• Mice MeSH
• Heart innervation   MeSH
• Sympathetic Nervous System metabolism   MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Hif1a protein, mouse MeSH Browser

The LIM homeodomain transcription factor ISL1 is essential for the different aspects of neuronal development and maintenance. In order to study the role of ISL1 in the auditory system, we generated a transgenic mouse (Tg) expressing Isl1 under the Pax2 promoter control. We previously reported a progressive age-related decline in hearing and abnormalities in the inner ear, medial olivocochlear system, and auditory midbrain of these Tg mice. In this study, we investigated how Isl1 overexpression affects sound processing by the neurons of the inferior colliculus (IC). We recorded extracellular neuronal activity and analyzed the responses of IC neurons to broadband noise, clicks, pure tones, two-tone stimulation and frequency-modulated sounds. We found that Tg animals showed a higher inhibition as displayed by two-tone stimulation; they exhibited a wider dynamic range, lower spontaneous firing rate, longer first spike latency and, in the processing of frequency modulated sounds, showed a prevalence of high-frequency inhibition. Functional changes were accompanied by a decreased number of calretinin and parvalbumin positive neurons, and an increased expression of vesicular GABA/glycine transporter and calbindin in the IC of Tg mice, compared to wild type animals. The results further characterize abnormal sound processing in the IC of Tg mice and demonstrate that major changes occur on the side of inhibition.

• Keywords
• auditory system, inferior colliculus, inhibition, sound processing, transcription factor ISL1,
• MeSH
• Inferior Colliculi metabolism   physiology   MeSH
• Gene Expression genetics   MeSH
• Humans MeSH
• Brain physiology   MeSH
• Mice, Transgenic MeSH
• Mice MeSH
• Neurons physiology   MeSH
• Promoter Regions, Genetic genetics   MeSH
• LIM-Homeodomain Proteins genetics   metabolism   MeSH
• Hearing MeSH
• Auditory Perception genetics   physiology   MeSH
• Evoked Potentials, Auditory, Brain Stem physiology   MeSH
• Auditory Threshold physiology   MeSH
• PAX2 Transcription Factor genetics   MeSH
• Transcription Factors genetics   metabolism   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Mice MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• insulin gene enhancer binding protein Isl-1 MeSH Browser
• PAX2 protein, human MeSH Browser
• Pax2 protein, mouse MeSH Browser
• LIM-Homeodomain Proteins MeSH
• PAX2 Transcription Factor MeSH
• Transcription Factors 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.

• Keywords
• cardiac innervation, coronary artery branching, hypoxia, sympathetic neurons, tyrosine hydroxylase,
• MeSH
• Coronary Vessel Anomalies embryology   MeSH
• Chromaffin Cells MeSH
• Adrenal Medulla embryology   innervation   MeSH
• Hypoxia-Inducible Factor 1, alpha Subunit physiology   MeSH
• Coronary Vessels embryology   MeSH
• Mice, Knockout MeSH
• Mice, Transgenic MeSH
• Mice MeSH
• Heart embryology   innervation   MeSH
• Ganglia, Sympathetic embryology   growth & development   MeSH
• Sympathetic Nervous System enzymology   growth & development   MeSH
• Animals MeSH
• Check Tag
• Male MeSH
• Mice MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Hypoxia-Inducible Factor 1, alpha Subunit MeSH
• Hif1a protein, mouse MeSH Browser

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.

• Keywords
• cardiomyopathy, embryopathy, fetal programing, heart development, hypoxia-inducible factor 1,
• Publication type
• Journal Article MeSH
• Review MeSH

BACKGROUND: Epidemiological studies show that maternal diabetes predisposes offspring to cardiovascular and metabolic disorders. However, the precise mechanisms for the underlying penetrance and disease predisposition remain poorly understood. We examined whether hypoxia-inducible factor 1 alpha, in combination with exposure to a diabetic intrauterine environment, influences the function and molecular structure of the adult offspring heart. METHODS AND RESULTS: In a mouse model, we demonstrated that haploinsufficient (Hif1a+/-) offspring from a diabetic pregnancy developed left ventricle dysfunction at 12 weeks of age, as manifested by decreased fractional shortening and structural remodeling of the myocardium. Transcriptional profiling by RNA-seq revealed significant transcriptome changes in the left ventricle of diabetes-exposed Hif1a+/- offspring associated with development, metabolism, apoptosis, and blood vessel physiology. In contrast, both wild type and Hif1a+/- offspring from diabetic pregnancies showed changes in immune system processes and inflammatory responses. Immunohistochemical analyses demonstrated that the combination of haploinsufficiency of Hif1a and exposure to maternal diabetes resulted in impaired macrophage infiltration, increased levels of advanced glycation end products, and changes in vascular homeostasis in the adult offspring heart. CONCLUSIONS: Together our findings provide evidence that a global reduction in Hif1a gene dosage increases predisposition of the offspring exposed to maternal diabetes to cardiac dysfunction, and also underscore Hif1a as a critical factor in the fetal programming of adult cardiovascular disease.

• Keywords
• Echocardiography, Fetal programming, Heart remodelling, Hif1a haploinsufficiency, Maternal diabetes,
• MeSH
• Diabetes Mellitus, Experimental complications   metabolism   pathology   MeSH
• Hypoxia-Inducible Factor 1, alpha Subunit genetics   metabolism   MeSH
• Ventricular Function, Left MeSH
• Diabetes, Gestational * metabolism   pathology   MeSH
• Haploinsufficiency MeSH
• Gene-Environment Interaction MeSH
• Cardiovascular Diseases genetics   metabolism   pathology   physiopathology   MeSH
• Mutation * MeSH
• Myocardium metabolism   pathology   MeSH
• Mice, Knockout MeSH
• Ventricular Remodeling MeSH
• Risk Factors MeSH
• Pregnancy MeSH
• Gene Expression Regulation, Developmental MeSH
• Prenatal Exposure Delayed Effects * MeSH
• Animals MeSH
• Check Tag
• Pregnancy MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Hypoxia-Inducible Factor 1, alpha Subunit MeSH
• Hif1a protein, mouse MeSH Browser

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.

• Keywords
• Diabetic complications, Diabetic nephropathy, Hypoxia, Mouse model, Podocyte,
• MeSH
• Diabetic Nephropathies etiology   metabolism   pathology   MeSH
• Diabetes Mellitus, Experimental complications   physiopathology   MeSH
• Hypoxia-Inducible Factor 1, alpha Subunit deficiency   genetics   MeSH
• Disease Models, Animal * MeSH
• Mice MeSH
• Prognosis MeSH
• Animals MeSH
• Check Tag
• Male MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Hypoxia-Inducible Factor 1, alpha Subunit MeSH
• Hif1a protein, mouse MeSH Browser

Male infertility is a worldwide problem associated with genetic background, environmental factors, and diseases. One of the suspected contributing factors to male infertility is diabetes mellitus. We investigated the molecular and morphological changes in sperms and testicular tissue of diabetic males. The study was performed in streptozotocin-induced type 1 diabetes mouse model. Diabetes decreased sperm concentration and viability and increased sperm apoptosis. Changes in protamine 1/protamine 2 ratio indicated reduced sperm quality. The testicular tissue of diabetic males showed significant tissue damage, disruption of meiotic progression, and changes in the expression of genes encoding proteins important for spermiogenesis. Paternal diabetes altered sperm quality and expression pattern in the testes in offspring of two subsequent generations. Our study revealed that paternal diabetes increased susceptibility to infertility in offspring through gametic alternations. Our data also provide a mechanistic basis for transgenerational inheritance of diabetes-associated pathologies since protamines may be involved in epigenetic regulations.

• MeSH
• Biomarkers MeSH
• Diabetes Mellitus, Type 1 complications   metabolism   MeSH
• Phenotype MeSH
• Genetic Predisposition to Disease * MeSH
• Meiosis MeSH
• Infertility, Male etiology   MeSH
• Mice MeSH
• Protamines metabolism   MeSH
• Spermatogenesis MeSH
• Spermatozoa metabolism   MeSH
• Testis metabolism   MeSH
• Inheritance Patterns * MeSH
• Animals MeSH
• Check Tag
• Male MeSH
• Mice MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Biomarkers MeSH
• Protamines MeSH

BACKGROUND: Diabetic cardiomyopathy is associated with a number of functional and structural pathological changes such as left ventricular dysfunction, cardiac remodeling, and apoptosis. The primary cause of diabetic cardiomyopathy is hyperglycemia, the metabolic hallmark of diabetes. Recent studies have shown that a diabetic environment suppresses hypoxia-inducible factor (HIF)-1α protein stability and function. The aim of this study was to analyze the functional role of HIF-1α in the development of diabetic cardiomyopathy. We have hypothesized that the partial deficiency of HIF-1α may compromise cardiac responses under diabetic conditions and increase susceptibility to diabetic cardiomyopathy. METHODS: Diabetes was induced by streptozotocin in wild type (Wt) and heterozygous Hif1a knock-out (Hif1a+/-) mice. Echocardiographic evaluations of left ventricular functional parameters, expression analyses by qPCR and Western blot, and cardiac histopathology assessments were performed in age-matched groups, diabetic, and non-diabetic Wt and Hif1a+/- mice. RESULTS: Five weeks after diabetes was established, a significant decrease in left ventricle fractional shortening was detected in diabetic Hif1a+/- but not in diabetic Wt mice. The combination effects of the partial deficiency of Hif1a and diabetes affected the gene expression profile of the heart, including reduced vascular endothelial growth factor A (Vegfa) expression. Adverse cardiac remodeling in the diabetic Hif1a+/- heart was shown by molecular changes in the expression of structural molecules and components of the extracellular matrix. CONCLUSIONS: We have shown a correlation between heterozygosity for Hif1α and adverse functional, molecular, and cellular changes associated with diabetic cardiomyopathy. Our results provide evidence that HIF-1α regulates early cardiac responses to diabetes, and that HIF-1α deregulation may influence the increased risk for diabetic cardiomyopathy.

• Publication type
• Journal Article MeSH