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Aim: The transcriptional factor HIF‐1α is recognized for its contribution to cardioprotection against acute ischemia/reperfusion injury. Adaptation to chronic hypoxia (CH) is known to stabilize HIF‐1α and increase myocardial ischemic tolerance. However, the precise role of HIF‐1α in mediating the protective effect remains incompletely understood. Methods: Male wild‐type (WT) mice and mice with partial Hif1a deficiency (hif1a+/−) were exposed to CH for 4 weeks, while their respective controls were kept under normoxic conditions. Subsequently, their isolated perfused hearts were subjected to ischemia/reperfusion to determine infarct size, while RNA‐sequencing of isolated cardiomyocytes was performed. Mitochondrial respiration was measured to evaluate mitochondrial function, and western blots were performed to assess mitophagy. Results: We demonstrated enhanced ischemic tolerance in WT mice induced by adaptation to CH compared with their normoxic controls and chronically hypoxic hif1a+/− mice. Through cardiomyocyte bulk mRNA sequencing analysis, we unveiled significant reprogramming of cardiomyocytes induced by CH emphasizing mitochondrial processes. CH reduced mitochondrial content and respiration and altered mitochondrial ultrastructure. Notably, the reduced mitochondrial content correlated with enhanced autophagosome formation exclusively in chronically hypoxic WT mice, supported by an increase in the LC3‐II/LC3‐I ratio, expression of PINK1, and degradation of SQSTM1/p62. Furthermore, pretreatment with the mitochondrial division inhibitor (mdivi‐1) abolished the infarct size‐limiting effect of CH in WT mice, highlighting the key role of mitophagy in CH‐induced cardioprotection. Conclusion: These findings provide new insights into the contribution of HIF‐1α to cardiomyocyte survival during acute ischemia/reperfusion injury by activating the selective autophagy pathway. [ABSTRACT FROM AUTHOR]

Hearing depends on extracting frequency, intensity, and temporal properties from sound to generate an auditory map for acoustical signal processing. How physiology intersects with molecular specification to fine tune the developing properties of the auditory system that enable these aspects remains unclear. We made a novel conditional deletion model that eliminates the transcription factor NEUROD1 exclusively in the ear. These mice (both sexes) develop a truncated frequency range with no neuroanatomically recognizable mapping of spiral ganglion neurons onto distinct locations in the cochlea nor a cochleotopic map presenting topographically discrete projections to the cochlear nuclei. The disorganized primary cochleotopic map alters tuning properties of the inferior colliculus units, which display abnormal frequency, intensity, and temporal sound coding. At the behavioral level, animals show alterations in the acoustic startle response, consistent with altered neuroanatomical and physiological properties. We demonstrate that absence of the primary afferent topology during embryonic development leads to dysfunctional tonotopy of the auditory system. Such effects have never been investigated in other sensory systems because of the lack of comparable single gene mutation models. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to examine whether variants in genes for transforming growth factor beta1 (TGF-beta1; Leu10>Pro and Arg25>Pro), plasminogen activator inhibitor 1 (PAI-1; 4G>5G variant) and collagen 1 (COL1A1; Sp1 variant) may be useful in identifying individuals with increased susceptibility to early postmenopausal bone loss within the population of Czech women., Methods: Polymorphisms were genotyped (by PCR and restriction analysis) in 1400 females representatively selected from the Czech population as well as in 218 postmenopausal osteoporotic women 40-70 years of age (mean age 58,7 years) and a 151 postmenopausal females within the same age range (mean age 59,1 years) with normal BMD., Results: We have not found any statistically significant differences in the frequency of individual genotypes or alleles of analyzed variants between the groups of osteoporotic patients (OP), population group (PG) and control group (CG). The frequency of the individual genotypes in the analyzed groups was as follows 1) TGF-beta1 gene: Leu10Leu10 OP 30.2 %, PG 35.6 %, CG 35.1 %; Leu10Pro10 OP 52.1 %, PG 47.1 %, CG 50.0 %; Pro10Pro10 OP 17.7 %, PG 17.3 %, CG 14.9 %; 2) TGF-beta1 gene Arg25 homozygotes OP 83.8 %, PG 86.1%, CG 89.3 %, Pro25 carriers OP 16.2 %, PG 13.9 %, CG 10.7 %, 3) PAI-1 gene: 4G4G OP 34.9 %, PG 31.8, CG 28.5 %, 5G4G OP 43.6 %, PG 46.7 %, CG 50.3 %, 5G5G OP 21.5 %, PG 21.5%, CG 21.2%, and 4) COL1A-1 ("SS" homozygotes, OP 63.0%, PG 63.7%, CG 64.6 %, "s" carriers OP 37.0 %, PG 36.3 %, CG 35.1 %)., Conclusions: Variants in genes for TGF-beta1 (Leu10>Pro and Arg25>Pro), PAI-1 (4G>5G) and COL1A1 (Sp1 variant) are not associated with low BMD in postmenopausal Czech Caucasian females.

Objective: The aim of this study was to examine whether the variants in genes for transforming growth factor beta1 (TGF-beta1; Leu10>Pro and Arg25>Pro), plasminogen activator inhibitor 1 (PAI-1; 4G>5G variant) and collagen -1 (COL1A-1; Sp1 variant) may be useful in identifying individuals with increased susceptibility to early postmenopausal bone loss within the population of Czech women., Methods: Polymorphisms were genotyped (by PCR and restriction analysis) in 1400 females representatively selected from the Czech population as well as in 218 postmenopausal osteoporotic women 40-70 years of age (mean age 58.7 years) and a 151 control group of postmenopausal females in the same age range (mean age 59.1 years) with normal BMD., Results: We have not found any statistically significant differences in the frequency of the individual genotypes or alleles of analyzed variants between the groups of osteoporotic patients (OP), population group (PG) and control group (CG). The frequencies of the individual genotypes in the analyzed groups were as follows - 1) TGF-beta1 gene: Leu10Leu10 OP - 30.2%, PG - 35.6%, CG 35.1%; Leu10Pro10 OP - 52.1%, PG - 47.1%, CG 50.0%; Pro10Pro10 OP - 17.7%, PG - 17.3%, CG 14.9%; 2) TGF-beta1 gene Arg25 homozygotes OP - 83.8%, PG - 86.1%, CG - 89.3%, Pro25 carriers OP - 16.2%, PG - 13.9%, CG - 10.7%, 3) PAI-1 gene: 4G4G OP - 34.9%, PG - 31.8, CG - 28.5%, 5G4G OP - 43.6%, PG - 46.7%, CG - 50.3%, 5G5G OP - 21.5%, PG - 21.5%, CG - 21.2%, and 4) COL1A-1 ("SS" homozygotes, OP - 63.0%, PG - 63.7%, - CG 64.9%, "s" carriers OP - 37.0%, PG - 36.3%, CG - 35.1%)., Conclusions: Variants in genes for TGF-beta1 (Leu10>Pro and Arg25>Pro), PAI-1 (4G>5G) and COL1A-1 (Sp1 variant) are not associated with low BMD in postmenopausal Czech Caucasian females.