Adverse effects of Hif1a mutation and maternal diabetes on the offspring heart

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F67985823%3A_____%2F18%3A00491883" target="_blank" >RIV/67985823:_____/18:00491883 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/86652036:_____/18:00491883 RIV/00216208:11110/18:10376797 RIV/00216208:11310/18:10376797

Výsledek na webu

<a href="http://dx.doi.org/10.1186/s12933-018-0713-0" target="_blank" >http://dx.doi.org/10.1186/s12933-018-0713-0</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1186/s12933-018-0713-0" target="_blank" >10.1186/s12933-018-0713-0</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Adverse effects of Hif1a mutation and maternal diabetes on the offspring heart

Popis výsledku v původním jazyce

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. nMethods 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 Hifia 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. nConclusions: Together our findings provide evidence that a global reduction in Hifia 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.

Název v anglickém jazyce

Adverse effects of Hif1a mutation and maternal diabetes on the offspring heart

Popis výsledku anglicky

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. nMethods 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 Hifia 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. nConclusions: Together our findings provide evidence that a global reduction in Hifia 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.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30105 - Physiology (including cytology)

Projekt

Výsledek vznikl pri realizaci vícero projektů. Více informací v záložce Projekty.

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2018

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Cardiovascular Diabetology

ISSN

1475-2840

e-ISSN

—

Svazek periodika

17

Číslo periodika v rámci svazku

MAY 12 2018

Stát vydavatele periodika

GB - Spojené království Velké Británie a Severního Irska

Počet stran výsledku

16

Strana od-do

—

Kód UT WoS článku

000432264400001

EID výsledku v databázi Scopus

2-s2.0-85046801833