Anomalous AMPK-regulated angiotensin AT1R expression and SIRT1-mediated mitochondrial biogenesis at RVLM in hypertension programming of offspring to maternal high fructose exposure

Autor: Kay L.H. Wu, Yung-Mei Chao, Pei-Chia Tsai, Julie Y.H. Chan, You-Lin Tain, Wei-Chia Lee, Steve Leu
Jazyk: angličtina
Rok vydání: 2020
Předmět:
0301 basic medicine
medicine.medical_specialty
Normal diet
Offspring
Endocrinology
Diabetes and Metabolism
Clinical Biochemistry
lcsh:Medicine
Angiotensin type 1 receptor
Fructose
030204 cardiovascular system & hematology
AMP-Activated Protein Kinases
Receptor
Angiotensin
Type 1
Rats
Sprague-Dawley
03 medical and health sciences
0302 clinical medicine
AMP-activated protein kinase
Programmed hypertension
Sirtuin 1
Internal medicine
medicine
Sirtuins
Animals
Pharmacology (medical)
Molecular Biology
NADPH oxidase
Organelle Biogenesis
biology
Chemistry
Research
lcsh:R
Biochemistry (medical)
AMPK
Cell Biology
General Medicine
Rostral ventrolateral medulla
TFAM
Mitochondria
Rats
030104 developmental biology
Endocrinology
Mitochondrial biogenesis
Gene Expression Regulation
Maternal Exposure
Hypertension
biology.protein
Maternal high fructose
Female
Zdroj: Journal of Biomedical Science
Journal of Biomedical Science, Vol 27, Iss 1, Pp 1-18 (2020)
ISSN: 1423-0127
1021-7770
Popis: BackgroundTissue oxidative stress, sympathetic activation and nutrient sensing signals are closely related to adult hypertension of fetal origin, although their interactions in hypertension programming remain unclear. Based on a maternal high-fructose diet (HFD) model of programmed hypertension, we tested the hypothesis that dysfunction of AMP-activated protein kinase (AMPK)-regulated angiotensin type 1 receptor (AT1R) expression and sirtuin1 (SIRT1)-dependent mitochondrial biogenesis contribute to tissue oxidative stress and sympathoexcitation in programmed hypertension of young offspring.MethodsPregnant female rats were randomly assigned to receive normal diet (ND) or HFD (60% fructose) chow during pregnancy and lactation. Both ND and HFD offspring returned to ND chow after weaning, and blood pressure (BP) was monitored from age 6 to 12 weeks. At age of 8 weeks, ND and HFD offspring received oral administration of simvastatin or metformin; or brain microinfusion of losartan. BP was monitored under conscious condition by the tail-cuff method. Nutrient sensing molecules, AT1R, subunits of NADPH oxidase, mitochondrial biogenesis markers in rostral ventrolateral medulla (RVLM) were measured by Western blot analyses. RVLM oxidative stress was measured by fluorescent probe dihydroethidium and lipid peroxidation by malondialdehyde assay. Mitochondrial DNA copy number was determined by quantitative real-time polymerase chain reaction.ResultsIncreased systolic BP, plasma norepinephrine level and sympathetic vasomotor activity were exhibited by young HFD offspring. Reactive oxygen species (ROS) level was also elevated in RVLM where sympathetic premotor neurons reside, alongside augmented protein expressions of AT1R and pg91phoxsubunit of NADPH oxidase, decrease in superoxide dismutase 2; and suppression of transcription factors for mitochondrial biogenesis, peroxisome proliferator-activated receptor γ co-activator α (PGC-1α) and mitochondrial transcription factor A (TFAM). Maternal HFD also attenuated AMPK phosphorylation and protein expression of SIRT1 in RVLM of young offspring. Oral administration of a HMG-CoA reductase inhibitor, simvastatin, or an AMPK activator, metformin, to young HFD offspring reversed maternal HFD-programmed increase in AT1R and decreases in SIRT1, PGC-1α and TFAM; alleviated ROS production in RVLM, and attenuated sympathoexcitation and hypertension.ConclusionDysfunction of AMPK-regulated AT1R expression and SIRT1-mediated mitochondrial biogenesis may contribute to tissue oxidative stress in RVLM, which in turn primes increases of sympathetic vasomotor activity and BP in young offspring programmed by excessive maternal fructose consumption.
Databáze: OpenAIRE
Externí odkaz: