Abstract
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 pg91phox subunit 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.
Highlights
Tissue oxidative stress, sympathetic activation and nutrient sensing signals are closely related to adult hypertension of fetal origin, their interactions in hypertension programming remain unclear
Dysfunction of AMP-activated protein kinase (AMPK)-regulated angiotensin type 1 receptor (AT1R) expression and SIRT1-mediated mitochondrial biogenesis may contribute to tissue oxidative stress in rostral ventrolateral medulla (RVLM), which in turn primes increases of sympathetic vasomotor activity and blood pressure (BP) in young offspring programmed by excessive maternal fructose consumption
Young offspring to maternal high fructose diet (HFD) exposure exhibit elevated blood pressure, augmented sympathetic vasomotor tone and higher circulatory norepinephrine level In comparison with normal diet (ND) group, baseline systolic blood pressure (SBP) (Fig. 1a), sympathetic vasomotor activity, as reflected by the power density of the Low frequency (LF) component of SBP signals (Fig. 1b), and circulatory NE level (Fig. 1c) were significantly increased in male, young offspring exposed to maternal HFD that became significant at age of 10 weeks
Summary
Sympathetic activation and nutrient sensing signals are closely related to adult hypertension of fetal origin, 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 sirtuin (SIRT1)-dependent mitochondrial biogenesis contribute to tissue oxidative stress and sympathoexcitation in programmed hypertension of young offspring. In a rodent model of DOHaD, we [8, 9] and others [10, 11] demonstrated that maternal exposure to a high fructose diet (HFD) during gestation and/or lactation programs the development of hypertension in adult offspring Both vascular and renal dysfunctions have been proposed as the culprits [12, 13], with enhanced reactive oxygen species (ROS) and reduced nitric oxide (NO) availability as the major protagonists [14, 15]. Angiotensin type 1 receptor (AT1R)-dependent activation of the nicotinamide adenine dinucleotide diphosphate oxidase (NADPH oxidase) signaling [18,19,20], suppression of endogenous antioxidants [18, 19, 21], impairment of mitochondrial biogenesis [18, 19, 22] and changes in protein expressions of NO synthase (NOS) isoforms [19, 23] have all been reported to contribute to the pathogenesis of hypertension via sympathoexcitation
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