Vasoactive Effects of Chronic Treatment with Fructose and Slow-Releasing H2S Donor GYY-4137 in Spontaneously Hypertensive Rats: The Role of Nitroso and Sulfide Signalization.

Increased fructose consumption induces metabolic-syndrome-like pathologies and modulates vasoactivity and the participation of nitric oxide (NO) and hydrogen sulfide (H2S). We investigated whether a slow-releasing H2S donor, GYY-4137, could exert beneficial activity in these conditions. We examined the effect of eight weeks of fructose intake on the blood pressure, biometric parameters, vasoactive responses, and NO and H2S pathways in fructose-fed spontaneously hypertensive rats with or without three weeks of GYY-4137 i.p. application. GYY-4137 reduced triacylglycerol levels and blood pressure, but not adiposity, and all were increased by fructose intake. Fructose intake generally enhanced endothelium-dependent vasorelaxation, decreased adrenergic contraction, and increased protein expression of interleukin-6 (IL-6), tumor necrosis factor alpha (TNFα), and concentration of conjugated dienes in the left ventricle (LV). Although GYY-4137 administration did not affect vasorelaxant responses, it restored disturbed contractility, LV oxidative damage and decreased protein expression of TNFα in fructose-fed rats. While the participation of endogenous H2S in vasoactive responses was not affected by fructose treatment, the expression of H2S-producing enzyme cystathionine ß-synthase in the LV was increased, and the stimulation of the NO signaling pathway improved endothelial function in the mesenteric artery. On the other hand, chronic treatment with GYY-4137 increased the expression of H2S-producing enzyme cystathionine γ-lyase in the LV and stimulated the beneficial pro-relaxant and anti-contractile activity of endogenous H2S in thoracic aorta. Our results suggest that sulfide and nitroso signaling pathways could trigger compensatory vasoactive responses in hypertensive rats with metabolic disorder. A slow H2S-releasing donor could partially amend metabolic-related changes and trigger beneficial activity of endogenous H2S.

Combined Therapy with Simvastatin- and Coenzyme-Q10-Loaded Nanoparticles Upregulates the Akt-eNOS Pathway in Experimental Metabolic Syndrome.

In addition to their LDL-cholesterol-lowering effect, statins have pleiotropic beneficial effects on the cardiovascular system. However, long-term treatment with statins may be associated with serious side effects. With the aim to make statin therapy more effective, we studied the effects of simvastatin- and coenzyme-Q10-loaded polymeric nanoparticles on the lipid profile and nitric oxide (NO)/reactive oxygen species (ROS) balance in the heart and aorta of adult male obese Zucker rats. The rats were divided into an untreated group, a group treated with empty nanoparticles, and groups treated with simvastatin-, coenzyme Q10 (CoQ10)-, or a combination of simvastatin- and CoQ10-loaded nanoparticles (SIMV+CoQ10). After 6 weeks, the lipid profile in the plasma and the concentration of conjugated dienes in the liver were determined. Nitric oxide synthase (NOS) activity, Akt, endothelial NOS (eNOS), phosphorylated eNOS (p-eNOS), nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, and nuclear factor kappaB (NF-kappaB) protein expressions were measured in the heart and aorta. All simvastatin, CoQ10, and SIMV+CoQ10 treatments decreased plasma LDL levels, but only the combined SIMV+CoQ10 treatment increased NOS activity and the expression of Akt, eNOS, and p-eNOS in both the heart and the aorta. Interestingly, NADPH oxidase in the heart and NF-kappaB protein expression in the aorta were decreased by all treatments, including nanoparticles alone. In conclusion, only combined therapy with SIMV- and CoQ10-loaded nanoparticles increased NOS activity and upregulated the Akt-eNOS pathway in obese Zucker rats, which may represent a promising tool for the treatment of cardiometabolic diseases.

Antioxidant Effect of Lonicera caerulea L. in the Cardiovascular System of Obese Zucker Rats.

Lonicera caerulea L. (Loni) represents a promising source of beneficial polyphenols with therapeutical potential in cardiovascular diseases. We aimed to study the effects of Loni and coenzyme Q10 (CoQ10) on selected cardiometabolic parameters and NO/ROS balance in obese Zucker rats. Male Zucker rats were divided into the control group and groups treated with CoQ10 (30 mg/kg/day) or Loni (5 g/kg/day) for 6 weeks. Blood pressure, body weight, heart weight, and plasma lipid profile were determined. NOS activity and protein expressions of eNOS, SOD, NADPH oxidase, and NF-kappa B were measured in the heart and aorta. Neither body weight nor blood pressure were significantly changed after six weeks of Loni or CoQ10 treatment. Both Loni and CoQ10 decreased the plasma LDL level. Moreover, Loni decreased the total cholesterol level. The total NOS activity did not change in the heart after the treatments. However, in the aorta, Loni treatment increased NOS activity and protein expression of SOD and decreased expressions of NADPH oxidase and NF-kappa B compared to both the control and CoQ10 groups. There were no changes in the eNOS protein expression within the groups. In conclusion, it seems that the antioxidant effect of Loni was responsible for both the decrease of plasma LDL and the total cholesterol levels and the increase of vascular NOS activity.

The Vasoactive Role of Perivascular Adipose Tissue and the Sulfide Signaling Pathway in a Nonobese Model of Metabolic Syndrome.

The aim of this study was to evaluate the mutual relationship among perivascular adipose tissue (PVAT) and endogenous and exogenous H2S in vasoactive responses of isolated arteries from adult normotensive (Wistar) rats and hypertriglyceridemic (HTG) rats, which are a nonobese model of metabolic syndrome. In HTG rats, mild hypertension was associated with glucose intolerance, dyslipidemia, increased amount of retroperitoneal fat, increased arterial contractility, and endothelial dysfunction associated with arterial wall injury, which was accompanied by decreased nitric oxide (NO)-synthase activity, increased expression of H2S producing enzyme, and an altered oxidative state. In HTG, endogenous H2S participated in the inhibition of endothelium-dependent vasorelaxation regardless of PVAT presence; on the other hand, aortas with preserved PVAT revealed a stronger anticontractile effect mediated at least partially by H2S. Although we observed a higher vasorelaxation induced by exogenous H2S donor in HTG rats than in Wistar rats, intact PVAT subtilized this effect. We demonstrate that, in HTG rats, endogenous H2S could manifest a dual effect depending on the type of triggered signaling pathway. H2S within the arterial wall contributes to endothelial dysfunction. On the other hand, PVAT of HTG is endowed with compensatory vasoactive mechanisms, which include stronger anti-contractile action of H2S. Nevertheless, the possible negative impact of PVAT during hypertriglyceridemia on the activity of exogenous H2S donors needs to be taken into consideration.

Health Effects of Grape Seed and Skin Extracts and Their Influence on Biochemical Markers.

This review is focused on the study of the effects of grape seed and skin extract (GSSE) on human health. GSSE contains high concentrations of important polyphenolic substances with high biological activity. This review is a summary of studies that investigate the effects of GSSE on diabetes mellitus, cardiovascular disease and cancer, its neuroprotective effect, and its effects on the gastrointestinal tract and other health complications related to these diseases. The results of the studies confirm that the anti-inflammatory, antiapoptotic, and pro-proliferative effects of "Vitis vinifera L." seed extract reduce the level of oxidative stress and improve the overall lipid metabolism.

Protective Effects of Polyphenols against Ischemia/Reperfusion Injury.

Myocardial infarction (MI) is a leading cause of morbidity and mortality across the world. It manifests as an imbalance between blood demand and blood delivery in the myocardium, which leads to cardiac ischemia and myocardial necrosis. While it is not easy to identify the first pathogenic cause of MI, the consequences are characterized by ischemia, chronic inflammation, and tissue degeneration. A poor MI prognosis is associated with extensive cardiac remodeling. A loss of viable cardiomyocytes is replaced with fibrosis, which reduces heart contractility and heart function. Recent advances have given rise to the concept of natural polyphenols. These bioactive compounds have been studied for their pharmacological properties and have proven successful in the treatment of cardiovascular diseases. Studies have focused on their various bioactivities, such as their antioxidant and anti-inflammatory effects and free radical scavenging. In this review, we summarized the effects and benefits of polyphenols on the cardiovascular injury, particularly on the treatment of myocardial infarction in animal and human studies.

Therapeutic Potential of Polyphenols-Loaded Polymeric Nanoparticles in Cardiovascular System.

Numerous studies document an increased production of reactive oxygen species (ROS) with a subsequent decrease in nitric oxide (NO) bioavailability in different cardiovascular diseases, including hypertension, atherosclerosis, and heart failure. Many natural polyphenols have been demonstrated to decrease ROS generation and/or to induce the endogenous antioxidant enzymatic defense system. Moreover, different polyphenolic compounds have the ability to increase the activity/expression of endothelial nitric oxide synthase (eNOS) with a subsequent enhancement of NO generation. However, as a result of low absorption and bioavailability of natural polyphenols, the beneficial effects of these substances are very limited. Recent progress in delivering polyphenols to the targeted tissues revealed new possibilities for the use of polymeric nanoparticles in increasing the efficiency and reducing the degradability of natural polyphenols. This review focuses on the effects of different natural polyphenolic substances, especially resveratrol, quercetin, curcumin, and cherry extracts, and their ability to bind to polymeric nanoparticles, and summarizes the effects of polyphenol-loaded nanoparticles, mainly in the cardiovascular system.

Simvastatin Does Not Affect Nitric Oxide Generation Increased by Sesame Oil in Obese Zucker Rats.

Current treatments for cardiovascular and obesity-associated diseases, such as statin therapy, may be associated with several side effects. Products from food sources with polyphenolic compounds may represent promising agents in the treatment of cardiovascular and metabolic diseases with minimal side effects. Thus, we aimed to study the effect of sesame oil and simvastatin treatment on plasma lipid profile, nitric oxide generation, and oxidative load in obese Zucker rats. 12-week-old male Zucker rats were divided into the control and sesame oil- (1.25 ml/kg/day) treated Zucker lean groups, the control and sesame oil (1.25 ml/kg/day), or simvastatin (15 mg/kg/day) together with sesame oil-treated Zucker fa/fa groups, n = 6 in each group. The treatment lasted for 6 weeks. Sesame oil composition and plasma lipid profile were analyzed. Nitric oxide synthase (NOS) activity, endothelial NOS (eNOS), phosphorylated eNOS, and inducible NOS (iNOS) protein expressions were determined in the left ventricle and aorta. Oxidative load, measured as conjugated diene (CD) and thiobarbituric acid reactive substance (TBARS) concentrations, was detected in the liver. Neither sesame oil nor cotreatment with simvastatin affected plasma lipid profile in Zucker fa/fa rats. Sesame oil and similarly cotreatment with simvastatin markedly increased NOS activity and phosphorylated eNOS protein expressions in the left ventricle and aorta of Zucker fa/fa rats. There were no changes in eNOS and iNOS protein expressions within the groups and tissues investigated. Hepatic CD concentration was higher in Zucker fa/fa comparing Zucker lean rats, and sesame oil treatment decreased it significantly. Interestingly, this decrease was not seen after cotreatment with simvastatin. In conclusion, phosphorylation of eNOS and decreased oxidative load may significantly contribute to increase in total NOS activity with potential beneficial properties. Interestingly, simvastatin did not affect NO generation already increased by sesame oil in obese Zucker rats.

Effect of Bioactive Compound of Aronia melanocarpa on Cardiovascular System in Experimental Hypertension.

Aronia melanocarpa has attracted scientific interest due to its dense contents of different polyphenols. We aimed to analyse effects of Aronia melanocarpa (AME) extract on blood pressure (BP), lipid peroxidation, cytokine level, total NOS activity in the left ventricle (LV), and aorta of L-NAME-induced hypertensive rats. 12-week-old male WKY rats were assigned to the control group and groups treated with AME extract (57.90 mg/kg/day), L-NAME (40 mg/kg/day), or combination of L-NAME (40 mg/kg/day) and AME (57.90 mg/kg/day) in tap water for 3 weeks. NOS activity, eNOS protein expression, and conjugated diene (CD) concentration were determined in the LV and aorta. After 3 weeks of L-NAME treatment, BP was increased by 28% and concomitant treatment with AME reduced it by 21%. NOS activity of the LV and aorta in the L-NAME group was decreased by about 40%, while AME increased it almost on the control level. AME-induced eNOS upregulation may contribute to increase NOS activity. Moreover, AME decreased CD concentration in the LV and aorta and TNF-α and IL-6 production in the plasma were increased by L-NAME treatment. In conclusion, our results showed that active substances of Aronia melanocarpa may have a positive effect on blood pressure, NOS activity, and proinflammatory processes in L-NAME-induced hypertension.

Red wine extract decreases pro-inflammatory markers, nuclear factor-κB and inducible NOS, in experimental metabolic syndrome.

We aimed to analyse the effects of alcohol-free Alibernet red wine extract (AWE) on nitric oxide synthase (NOS) activity and pro-inflammatory markers such as nuclear factor-κB (NFκB) and inducible NOS (iNOS) protein expression in experimental metabolic syndrome. Young 6 week-old male Wistar Kyoto (WKY) and obese, spontaneously hypertensive rats (SHR/N-cp) were divided into control groups and groups treated with AWE (24.2 mg per kg per day) for 3 weeks (n = 6 in each group). Total NOS activity and endothelial NOS (eNOS), iNOS and NFκB (p65) protein expressions were determined in the heart left ventricle and aorta by Western blot and immunohistochemical analysis. All parameters investigated significantly increased in the aorta of SHR/N-cp rats. Pro-inflammatory markers such as NFκB and iNOS were increased in the left ventricle as well. AWE treatment did not affect total NOS activity and eNOS expression in the aorta; however, it was able to decrease NFκB and iNOS protein expression in both the left ventricle and aorta. In conclusion, in the cardiovascular system, Alibernet red wine extract decreased NFκB and iNOS protein expressions elevated as a consequence of developed metabolic syndrome. This effect may represent one of the protective, anti-inflammatory properties of Alibernet red wine polyphenols on cardiovascular risk factors related to metabolic syndrome.