Fructose Intake Impairs the Synergistic Vasomotor Manifestation of Nitric Oxide and Hydrogen Sulﬁde in Rat Aorta

International Journal of Molecular Sciences Article Fructose Intake Impairs the Synergistic Vasomotor Manifestation of Nitric Oxide and Hydrogen Sulfide in Rat Aorta Andrea Berenyiova *, Samuel Golas, Magdalena Drobna, Martina Cebova and Sona Cacanyiova Institute of Normal and Pathological Physiology, Centre of Experimental Medicine Slovak Academy of Sciences, 841 04 Bratislava, Slovakia; [email protected] (S.G.); [email protected] (M.D.); [email protected] (M.C.); [email protected] (S.C.) * Correspondence: [email protected] Abstract: In this study, we evaluated the effect of eight weeks of administration of 10% fructose solution to adult Wistar Kyoto (WKY) rats on systolic blood pressure (SBP), plasma and biometric parameters, vasoactive properties of the thoracic aorta (TA), NO synthase (NOS) activity, and the expression of enzymes producing NO and H2S. Eight weeks of fructose administration did not affect SBP, glycaemia, or the plasma levels of total cholesterol or low-density and high-density lipoprotein; however, it significantly increased the plasma levels of γ-glutamyl transferase and alanine transaminase. Chronic fructose intake deteriorated endothelium-dependent vasorelaxation (EDVR) and increased the sensitivity of adrenergic receptors to noradrenaline. Acute NOS inhibition evoked a reduction in EDVR that was similar between groups; however, it increased adrenergic contraction more in fructose-fed rats. CSE inhibition decreased EDVR in WKY but not in fructose-fed Citation: Berenyiova, A.; Golas, S.; rats. The application of a H2S scavenger evoked a reduction in the EDVR in WKY rats and normalized Drobna, M.; Cebova, M.; Cacanyiova, the sensitivity of adrenergic receptors in rats treated with fructose. Fructose intake did not change S. Fructose Intake Impairs the NOS activity but reduced the expression of eNOS and CBS in the TA and CSE and CBS in the left Synergistic Vasomotor Manifestation ventricle. Based on our results, we could assume that the impaired vascular function induced by of Nitric Oxide and Hydrogen Sulfide increased fructose intake was probably not directly associated with a decreased production of NO, in Rat Aorta. Int. J. Mol. Sci. 2021, 22, 4749. https://doi.org/10.3390/ijms but rather with impairment of the NO–H2S interaction and its manifestation in vasoactive responses. 22094749 Keywords: fructose; Wistar Kyoto rats; thoracic aorta; nitric oxide; hydrogen sulfide Academic Editor: Marcin Magierowski Received: 6 April 2021 1. Introduction Accepted: 27 April 2021 Currently, significant changes in nutritional habits present an important factor en- Published: 30 April 2021 croaching into the equilibrium of different signaling pathways in the body. Excessive intake of added sugars, mainly as sugar-sweetened beverages, has been implicated in the Publisher’s Note: MDPI stays neutral development of obesity and metabolic disturbances, increasing the risk of cardiovascular with regard to jurisdictional claims in disease mortality. Two major sweeteners are predominantly used in the food and bev- published maps and institutional affil- erage industry: sucrose, a disaccharide containing 50% fructose and 50% glucose; and iations. high-fructose corn syrup, which mainly consists of 55% fructose and 45% glucose [1,2]. Fructose is a natural, simple sugar found in fruits and honey that is responsible for their sweet taste. Due to its specific metabolism, predominantly in the liver, fructose is more lipogenic than glucose. Long-term application of this saccharide at different concentrations Copyright: © 2021 by the authors. in food or drinking water has been used to induce metabolic disorders in experimental Licensee MDPI, Basel, Switzerland. models [3]. Animals chronically receiving high amounts of fructose developed hypertriglyc- This article is an open access article eridemia, insulin resistance, hyperinsulinemia, and often obesity and hypertension [4–6]. distributed under the terms and Zemancikova and Torok (2014) [7] also reported that eight weeks of fructose administration conditions of the Creative Commons to adult Wistar rats induced metabolic changes associated with an increase in plasma Attribution (CC BY) license (https:// glucose and lipids, enlargement of the liver, significant blood pressure elevation, and creativecommons.org/licenses/by/ reduction in endothelium-derived vasorelaxation. The authors also pointed out the specific 4.0/). Int. J. Mol. Sci. 2021, 22, 4749. https://doi.org/10.3390/ijms22094749 https://www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 2 of 18 in plasma glucose and lipids, enlargement of the liver, significant blood pressure elevation, and reduction in endothelium-derived vasorelaxation. The authors also pointed out the specific role of NO/NOS signaling in these processes, because simultaneous treatment with a NOS inhibitor and fructose did not evoke the abovementioned pathological changes. Literary data show that another gaseous molecule, endogenously synthesized hydro- Int. J. Mol. Sci. 2021, 22, 4749 2 of 17 gen sulfide (H2S), is involved in the same biological processes as NO, including the vasomotor responses of the arterial wall, neurotransmission, control of infectious processes, and insulin release [8,9]. Pan et al. (2014) [10] demonstrated that a high-saccharide envi- role of NO/NOS signaling in these processes, because simultaneous treatment with a NOS ronmentinhibitor andinhibits fructose the did expression not evoke theof abovementionedone of the H2S-producing pathological changes.enzymes, cystathionine-γ- lyaseLiterary (CSE), datain adipocytes. show that another Several gaseous studies molecule, have also endogenously suggested synthesizedthat high glucose hy- intake significantlydrogen sulfide increases (H2S), is involvedthe secretion in the sameof pro-inflammatory biological processes cytokines, as NO, including including the tumor ne- crosisvasomotor factor- responsesα (TNF- ofα the), IL-6, arterial and wall, monocyte neurotransmission, chemoattractant control of protein-1 infectious processes, [11,12], and the in- and insulin release [8,9]. Pan et al. (2014) [10] demonstrated that a high-saccharide environ- volved mechanism is partly related to inhibition of the CSE/H2S system. ment inhibits the expression of one of the H2S-producing enzymes, cystathionine-γ-lyase Based on this, we can assume that the endogenous NO and H2S signaling pathways (CSE), in adipocytes. Several studies have also suggested that high glucose intake signif- couldicantly be increases involved the in secretion the metabolic of pro-inflammatory disorders caused cytokines, by high including saccharide tumor necrosis intake. However, thefactor- dataα (TNF- relatedα), IL-6,to their and vasoregulatory monocyte chemoattractant mechanisms protein-1 in this [11 ,12circumstance], and the involved are still limited. Themechanism main goal is partly of the related present to inhibition study was of the to CSE/H describe2S system. the effect of eight weeks of fructose administrationBased on this, to weadult can Wistar assume thatKyoto the (WKY) endogenous rats NOon the and vasoactive H2S signaling properties pathways of the tho- could be involved in the metabolic disorders caused by high saccharide intake. However, racic aorta, with special emphasis on the participation of NO and H2S signaling pathways. the data related to their vasoregulatory mechanisms in this circumstance are still limited. SuchThe main observations goal of the have present so studyfar not was been to describe made. We the effecthypothesized of eight weeks that ofthe fructose increased intake ofadministration fructose induces to adult metabolic Wistar Kyoto syndrome-like (WKY) rats on thedisorders vasoactive that properties could ofprobably the thoracic modulate the NOaorta, and with H special2S signaling emphasis pathways on the participation and their ofinteraction. NO and H2 S signaling pathways. Such observations have so far not been made. We hypothesized that the increased intake of 2.fructose Results induces metabolic syndrome-like disorders that could probably modulate the NO and H S signaling pathways and their interaction. 2.1. Blood2 Pressure, Cardiac Hypertrophy, Weight Gain, and Fluid and Food Intake 2. ResultsLong-term increased fructose intake had a significant effect on the values of systolic 2.1. Blood Pressure, Cardiac Hypertrophy, Weight Gain, and Fluid and Food Intake blood pressure (SBP) (F(1;219) = 14.25; p = 2.09 × 10−4); however, the statistical analysis did not revealLong-term any increaseddifferences fructose between intake the had experi a significantmental effect groups on the in valuesindividual of systolic weeks (Figure blood pressure (SBP) (F = 14.25; p = 2.09 × 10−4); however, the statistical analysis did 1). Fructose treatment(1;219) had no impact on the parameters of heart trophicity; neither the not reveal any differences between the experimental groups in individual weeks (Figure1 ). ratioFructose of heart treatment weight had noto impactbody weight on the parameters nor the tibial of heart length trophicity; to body neither weight the ratio were changed afterof heart fructose weight treatment to body weight (Table nor 1). the Surprising tibial lengthly, tothe body eight-week weight were fructose changed treatment after did not affectfructose the treatment weight (Table gain1 ).or Surprisingly, adiposity the(expressed eight-week as fructose a ratio treatment of the retroperitoneal did not affect adipose tissuethe weight weight gain to or the

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