Kaempferol protects against cardiovascular abnormalities induced by nitric oxide deficiency in rats by suppressing the TNF-α pathway.

Kaempferol is a natural flavonoid compound that exhibits various pharmacological actions. However, there are few reports regarding the role of kaempferol in cardiovascular abnormalities. This study aimed to assess whether kaempferol could prevent cardiovascular malfunction and hypertrophy provoked by chronic inhibition of nitric oxide (NO) formation in rats. Rats (180-200 g) were treated daily with Nω-nitro-L-arginine methyl ester hydrochloride (L-NAME) (40 mg/kg, in drinking water) for five weeks concomitant with kaempferol (oral administration) at a dose of 20 mg/kg or 40 mg/kg or lisinopril (5 mg/kg). Kaempferol partially prevented the progression of hypertension provoked by NO inhibition (p < 0.05). Left ventricular malfunction and hypertrophy present in hypertensive rats were alleviated by concurrent administration of kaempferol (p < 0.05). Furthermore, L-NAME rats had increased sympathetic nerve-mediated vasoconstriction and decreased acetylcholine-induced vasorelaxation and aortic wall thickening, which were resolved by kaempferol treatment (p < 0.05). Kaempferol restored tissue superoxide formation, malondialdehyde, catalase activity, plasma nitric oxide metabolites, tumor necrosis factor-alpha (TNF-α) and interleukin-6 in L-NAME rats (p < 0.05). Overexpression of tumor necrosis factor receptor 2 (TNFR2), phosphatidylinositol 3-kinases (PI3K), AKT serine/threonine kinase 1 (Akt1) and smad2/3 in heart tissue and upregulation of tumor necrosis factor receptor 1 (TNFR1), phosphorylated nuclear factor-kappaB (p-NF-κB) and transforming growth factor beta 1 (TGF-ß1) in vascular tissue were suppressed by kaempferol (p < 0.05). In conclusion, kaempferol exerts antihypertensive, cardioprotective, antioxidant, and anti-inflammatory effects in NO-dependent hypertensive rats. The underlying mechanisms of kaempferol in preventing cardiovascular changes induced by L-NAME were due to the suppression of the TNF-α pathway.

Cardiovascular complications are resolved by tuna protein hydrolysate supplementation in rats fed with a high-fat diet.

This study is aimed to investigate whether tuna protein hydrolysate (TPH) supplementation could alleviate cardiovascular complications induced by a high-fat diet (HFD) in rats. Rats were fed a HFD for 16 weeks and given TPH (100 mg/kg, 300 mg/kg, or 500 mg/kg) or metformin (100 mg/kg) (n = 8) for the last four weeks. TPH had the following effects: resolved their impaired glucose tolerance, hyperglycemia, dyslipidemia, obesity, and hypertension (p < 0.05); alleviated left ventricular dysfunction and hypertrophy (p < 0.05), and vascular dysfunction and hypertrophy (p < 0.05); adipocyte hypertrophy; increases in circulating leptin and tumor necrosis factor (TNF-α) were mitigated (p < 0.05); increased renin-angiotensin system (RAS), oxidative stress, and decreased nitric oxide metabolites were modulated (p < 0.05). TPH restored the expression of angiotensin II receptor type 1 (AT1R)/NADPH oxidase 2 (NOX2), endothelial nitric oxide synthase (eNOS), nuclear factor erythroid 2-related factor (Nrf2)/heme oxygenase-1 (HO-1), and peroxisome proliferator-activated receptor γ (PPARγ)/the nuclear factor kappa B (NF-κB) protein in cardiovascular tissue (p < 0.05). In metabolic syndrome (MS) rats, metformin and TPH had comparable effects. In conclusion, TPH alleviated cardiovascular complications related to MS. It suppressed RAS, oxidative stress, and inflammation that were associated with modulation of AT1R/NOX2, eNOS, Nrf2/HO-1, and PPARγ/NF-κB expression.

Limonin ameliorates cardiovascular dysfunction and remodeling in hypertensive rats.

AIMS: Limonin is a tetracyclic triterpenoid isolated from citrus fruits. Here, the effects of limonin on cardiovascular abnormalities in nitric oxide-deficient rats induced by Nω-Nitrol-arginine methyl ester (L-NAME) were explored. MAIN METHODS: Male Sprague Dawley rats were given L-NAME (40 mg/kg, drinking water) for 3 weeks and then treated daily with polyethylene glycol (vehicle), limonin (50 or 100 mg/kg) or telmisartan (10 mg/kg) for two weeks. KEY FINDINGS: Limonin (100 mg/kg) markedly reduced L-NAME-induced hypertension, cardiovascular dysfunction and remodeling in rats (P < 0.05). Increases in systemic angiotensin-converting enzyme (ACE) activity and angiotensin II (Ang II) and a reduction in circulating ACE2 were restored in hypertensive rats treated with limonin (P < 0.05). Reductions in antioxidant enzymes and nitric oxide metabolites (NOx) and increases in oxidative stress components induced by L-NAME were relieved by limonin treatment (P < 0.05). Limonin suppressed the increased expression of tumor necrosis factor-α (TNF-α) and interleukin (IL)-6 in cardiac tissue and circulating TNF-α in rats that received L-NAME (P < 0.05). Changes in Ang II receptor type I (AT1R), Mas receptor (MasR), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-ĸB) and NADPH oxidase subunit 2 (gp91phox) protein expression in cardiac and aortic tissue were normalized by limonin (P < 0.05). SIGNIFICANCE: In conclusion, limonin ameliorated L-NAME-induced hypertension, cardiovascular dysfunction and remodeling in rats. These effects were relevant to restorations of the renin-angiotensin system, oxidative stress and inflammation in NO-deficient rats. The molecular mechanisms are associated with the modulation of AT1R, MasR, NF-ĸB and gp91phox protein expression in cardiac and aortic tissue.

Limonin mitigates cardiometabolic complications in rats with metabolic syndrome through regulation of the IRS-1/GLUT4 signalling pathway.

Limonin is a natural triterpenoid isolated from citrus fruit. In the present study, we examined the effects of limonin on cardiometabolic alterations in diet-induced metabolic syndrome. Metabolic syndrome was induced in rats by feeding them a high-fat (HF) diet plus 15% fructose in drinking water for 16 weeks. They were treated with limonin (50 or 100 mg/kg) (n = 8/group) for the final 4 weeks. Increases in body weight (BW), fasting blood glucose (FBG), serum insulin, total cholesterol (TC), blood pressure (BP), liver fat accumulation, and adipocyte hypertrophy, as well as oral glucose tolerance in rats with metabolic syndrome were alleviated by limonin treatment (p < 0.05). Limonin improved ejection fraction and left ventricular (LV) hypertrophy, and reduced angiotensin converting enzyme (ACE) activity and angiotensin II (Ang II) concentration in rats with metabolic syndrome (p < 0.05). It also reduced plasma tumour necrosis factor (TNF)-α, interleukin (IL)- 6, leptin, malonaldehyde (MDA), and superoxide generation, and increased catalase activity in rats with metabolic syndrome compared to controls (p < 0.05). Downregulation of insulin receptor substrate 1 (IRS-1) and glucose transporter type 4 (GLUT4) protein expression in epididymal fat pads and cardiac, liver, and gastrocnemius tissues was present in metabolic syndrome, and these were restored by limonin treatment (p < 0.05). In conclusion, limonin shows a potential effect in alleviating symptoms and improving cardiometabolic disorders. These beneficial effects are linked to the reduction of the renin-angiotensin system, inflammation, oxidative stress, and improvement of IRS-1/GLUT4 protein expression in the target tissue.

Cardiorenal dysfunction and hypertrophy induced by renal artery occlusion are normalized by galangin treatment in rats.

Galangin is a polyphenolic compound found in Alpinia officinarum and propolis. This study investigated the effect of galangin on blood pressure, the renin angiotensin system (RAS), cardiac and kidney alterations and oxidative stress in two-kidney one-clipped (2K-1C) hypertensive rats. Hypertension was induced in male Sprague Dawley rats (180-220 g), and the rats were given galangin (30 and 60 mg/kg) and losartan (10 mg/kg) for 4 weeks (n = 8/group). Galangin decreased hypertension and cardiac dysfunction and hypertrophy, which was related to the reducing circulation angiotensin converting enzyme (ACE) activity and angiotensin II concentration (p < 0.05). These effects were consistent with the reduced overexpression of angiotensin II receptor type 1 (AT1R), transforming growth factor beta 1 (TGF-ß1) and collagen type I (Col I) protein in cardiac tissue (p < 0.05). Additionally, renal artery occlusion, procedure-induced kidney dysfunction and fibrosis were attenuated in the galangin-treated group. Galangin treatment normalized the overexpression of AT1R and NADPH oxidase 4 (Nox-4) protein and normalized the downregulation of nuclear factor-erythroid Factor 2-related Factor 2 (Nrf-2) and haem oxygenase 1 (HO-1) in 2K-1C rats (p < 0.05). Galangin exhibited antioxidative effects, as it reduced systemic and tissue oxidative stress markers and increased catalase activity in 2K-1C rats (p < 0.05). In conclusion, galangin attenuated hypertension, renin-angiotensin system activation, cardiorenal damage and oxidative stress induced by renal artery stenosis in rats. These effects might be associated with modulation of the expression of AT1R, TGF-ß1 and Col I protein in the heart as well as AT1R/Nox-4 and Nrf-2/HO-1 protein in renal tissue in hypertensive rats.

Nobiletin resolves left ventricular and renal changes in 2K-1C hypertensive rats.

This study investigated the effects of nobiletin on cardiorenal changes and the underlying mechanisms involved in two-kidney, one-clip (2K-1C) hypertension. 2K-1C rats were treated with nobiletin (15 or 30 mg/kg/day) or losartan (10 mg/kg/day) for 4 weeks (n = 8/group). Nobiletin (30 mg/kg) reduced high levels of blood pressure and circulating angiotensin II and angiotensin-converting enzyme activity in 2K-1C rats. Left ventricular (LV) dysfunction and remodelling in 2K-1C rats were alleviated in the nobiletin-treated group (P < 0.05). Nobiletin reduced the upregulation of Ang II type I receptor (AT1R)/JAK (Janus kinase)/STAT (signal transducer and activator of transcription) protein expression in cardiac tissue of 2K-1C rats (P < 0.05). The reduction in kidney function, and accumulation of renal fibrosis in 2K-1C rats were alleviated by nobiletin (P < 0.05). Overexpression of AT1R and NADPH oxidase 4 (Nox4) protein in nonclipped kidney tissue was suppressed in the nobiletin-treated group (P < 0.05). The elevations in oxidative stress parameters and the reductions in antioxidant enzymes were attenuated in 2K-1C rats treated with nobiletin (P < 0.05). In summary, nobiletin had renin-angiotensin system inhibitory and antioxidant effects and attenuated LV dysfunction and remodelling via restoration of the AT1R/JAK/STAT pathway. Nobiletin also resolved renal damage that was related to modulation of the AT1R/Nox4 cascade in 2K-1C hypertension.

Imperatorin attenuates cardiac remodelling and dysfunction in high-fat/high-fructose diet-fed rats by modulating oxidative stress, inflammation, and Nrf-2 expression.

Imperatorin, an active natural furocoumarin, exerts a wide range of biological activities. In the present study, the therapeutic effects of imperatorin on cardiac function and remodelling and the possible underlying mechanisms involved in high-fat/high-fructose diet (HFFD)-fed rats were investigated. Male Sprague-Dawley rats were fed a high-fat diet plus 15 % fructose in drinking water for 16 weeks. HFFD-fed rats were treated with imperatorin (15 or 30 mg/kg/day) for the last 4 weeks. Treatment of HFFD-fed rats with imperatorin significantly reduced dyslipidaemia, hyperinsulinaemia, and hypertension. Imperatorin markedly alleviated HFFD-induced cardiac morphology alterations and left ventricular (LV) dysfunction. Imperatorin also significantly decreased malondialdehyde concentration and increased catalase activity in plasma and cardiac tissue. Additionally, decreased plasma tumour necrosis factor-α and interleukin-6 concentrations, together with restoration of cardiac nuclear factor-erythroid 2-related factor 2 (Nrf-2) protein expression, were also observed after treatment with imperatorin. These findings indicated that imperatorin alleviates HFFD-induced cardiac remodelling and LV dysfunction in rats. The possible underlying mechanism may involve the reduction of oxidative stress and inflammation, and the restoration of Nrf-2 expression.

Galangin Resolves Cardiometabolic Disorders through Modulation of AdipoR1, COX-2, and NF-κB Expression in Rats Fed a High-Fat Diet.

Galangin is a natural flavonoid. In this study, we evaluated whether galangin could alleviate signs of metabolic syndrome (MS) and cardiac abnormalities in rats receiving a high-fat (HF) diet. Male Sprague-Dawley rats were given an HF diet plus 15% fructose for four months, and they were fed with galangin (25 or 50 mg/kg), metformin (100 mg/kg), or a vehicle for the last four weeks. The MS rats exhibited signs of MS, hypertrophy of adipocytes, impaired liver function, and cardiac dysfunction and remodeling. These abnormalities were alleviated by galangin (p < 0.05). Interleukin-6 and tumor necrosis factor-α concentrations and expression were high in the plasma and cardiac tissue in the MS rats, and these markers were suppressed by galangin (p < 0.05). These treatments also alleviated the low levels of adiponectin and oxidative stress induced by an HF diet in rats. The downregulation of adiponectin receptor 1 (AdipoR1) and cyclooxygenase-2 (COX-2) and the upregulation of nuclear factor kappa B (NF-κB) expression were recovered in the galangin-treated groups. Metformin produced similar effects to galangin. In conclusion, galangin reduced cardiometabolic disorders in MS rats. These effects might be linked to the suppression of inflammation and oxidative stress and the restoration of AdipoR1, COX-2, and NF-κB expression.

Butterfly Pea Flower (Clitoria ternatea Linn.) Extract Ameliorates Cardiovascular Dysfunction and Oxidative Stress in Nitric Oxide-Deficient Hypertensive Rats.

In this study, we examine whether Clitoria ternatea Linn. (CT) can prevent Nω-nitro-L-arginine methyl ester hydrochloride (L-NAME)-induced cardiac and vascular dysfunction in rats. Male Sprague Dawley rats were given L-NAME (40 mg/kg, drinking water) and orally administered with CT extract (300 mg/kg/day) or lisinopril (2.5 mg/kg/day) for 5 weeks. The main phytochemical components of the CT extract were found to be flavonoids. The CT extract alleviated the high blood pressure in rats receiving L-NAME. Decreased vasorelaxation responses to acetylcholine and enhanced contractile responses to sympathetic nerve stimulation in aortic rings and mesenteric vascular beds of L-NAME treated rats were ameliorated by CT extract supplementation. Left ventricular hypertrophy and dysfunction were developed in L-NAME rats, which were partially prevented by CT extract treatment. The CT extract alleviated upregulated endothelial nitric oxide synthase expression, decreased plasma nitrate/nitrite levels, and increased oxidative stress in L-NAME rats. It suppressed high levels of serum angiotensin-converting enzyme activity, plasma angiotensin II, and cardiac angiotensin II type 1 receptor, NADPH oxidases 2, nuclear factor-kappa B, and tumor necrosis factor-alpha expression. The CT extract, therefore, partially prevented L-NAME-induced hypertension and cardiovascular alterations in rats. These effects might be related to a reduction in the oxidative stress and renin-angiotensin system activation due to L-NAME in rats.

Genistein Prevents Nitric Oxide Deficiency-Induced Cardiac Dysfunction and Remodeling in Rats.

Genistein is an isoflavone found in soybeans. This study evaluates the protective effects of genistein on Nω-nitro-L-arginine methyl ester hydrochloride (L-NAME)-induced hypertension, cardiac remodeling, and dysfunction in rats. Male Wistar rats were treated with L-NAME 40 mg/kg/day together for 5 weeks, with or without genistein at a dose of 40 or 80 mg/kg/day or lisinopril 5 mg/kg/day (n = 8 per group). Genistein prevented L-NAME-induced hypertension in rats. Increases in the left ventricular weight, metalloproteinase-2, metalloproteinase-9, and collagen type I intensity were observed in L-NAME rats, and these changes were attenuated in the genistein-treated group. Genistein reduced circulating angiotensin-converting enzyme activity and angiotensin II concentrations in L-NAME rats. L-NAME increased plasma and cardiac malondialdehyde and vascular superoxide generations, as well as reductions of serum and cardiac catalase activities in rats. Plasma nitrate/nitrite were protected in the genistein-treated group. Genistein prevented the L-NAME-induced overexpression of angiotensin II receptor type I (AT1R), nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunit 2 (gp91phox), and transforming growth factor beta I (TGF-ß1) in hypertensive rats. In conclusion, genistein exhibited a cardioprotective effect in hypertensive rats in this study. The molecular mechanisms might be mediated by suppression of oxidative stress through the Ang II/AT1R/NADPH oxidase/TGF-ß1 signaling pathway.

Diosmetin attenuates metabolic syndrome and left ventricular alterations via the suppression of angiotensin II/AT1 receptor/gp91phox/p-NF-κB protein expression in high-fat diet fed rats.

Diosmetin, a monomethoxyflavone, is isolated from citrus fruits. The objective of this research was to test the biological role of diosmetin on parameters of metabolic syndrome (MS) and left ventricular (LV) alterations in rats fed with a high-fat (HF) diet. MS was induced by feeding male Sprague-Dawley rats with a HF diet plus 15% fructose in drinking water for 16 weeks. MS rats were given diosmetin (20 or 40 mg per kg per day) or metformin (100 mg per kg per day) for the final four weeks. Diosmetin attenuated signs of MS including, hypertension, hyperglycemia, insulin resistance, and dyslipidemia in rats that received the HF diet (p < 0.05). A decreased stroke volume, ejection fraction, fractional shortening, LV hypertrophy and fibrosis present in the MS group were alleviated by diosmetin treatment (p < 0.05). Diosmetin also suppressed angiotensin-converting enzyme activity, plasma angiotensin II (Ang II) levels and angiotensin II type 1 (AT1) receptor protein expression in MS rats. Increases in superoxide (O2˙-) formation, plasma malondialdehyde, plasma nitrate and nitrite and gp91phox expression induced by a HF diet were ameliorated in the diosmetin treated group. Inflammation indicated by an increased phospho nuclear factor kappa B (p-NF-κB) protein expression and cardiac TNF-α concentration was reduced in MS rats receiving diosmetin (p < 0.05). Metformin also attenuated MS, cardiac abnormalities relevant to decreasing the renin-angiotensin system stimulation, reactive oxygen species and inflammation in MS rats (p < 0.05). Diosmetin alleviated MS and LV dysfunction and remodeling in HF diet-induced MS rats. These results could be associated with the suppression of the Ang II/AT1 receptor/gp91phox/p-NF-κB protein pathway.

Hesperidin ameliorates signs of the metabolic syndrome and cardiac dysfunction via IRS/Akt/GLUT4 signaling pathway in a rat model of diet-induced metabolic syndrome.

BACKGROUND: Hesperidin has been reported to have biological activities such as antihypertensive, hypoglycemic, and antioxidant effects. This study investigated whether hesperidin could improve signs of the metabolic syndrome and cardiac function in a high-fat diet (HFD) induced metabolic syndrome (MS) in rats. METHODS: Male Sprague-Dawley rats were fed HFD and 15% fructose for 16 weeks and treated with hesperidin (15 or 30 mg/kg, based on signs of MS from a preliminary study) or metformin, a positive control agent, (100 mg/kg) for the final four weeks. Cardiac function, blood pressure, fasting blood glucose, oral glucose tolerance, serum insulin, and lipid profiles were measured. Histomorphometrics of left ventricles, epidydimal fat pads and liver were evaluated. Expressions of phosphorylate insulin receptor substrate1(p-IRS1), p-Akt and GLUT4 in cardiac tissue were determined. RESULTS: Hesperidin and metformin attenuated MS in HFD rats (p < 0.05). The accumulation of visceral fat pads and fatty liver associated with increases in liver lipid contents and liver enzymes were found in MS rats that were alleviated in hesperidin or metformin-treated groups (p < 0.05). Hesperidin and metformin improved cardiac dysfunction and hypertrophy observed in MS rats (p < 0.05). Restoration of the insulin signaling pathway, IRS/Akt/GLUT4 protein expression, was demonstrated in hesperidin and metformin-treated groups (p < 0.05). Hesperidin (30 mg/kg) was more effective than the lower dose. CONCLUSION: Hesperidin was effective in reducing signs of MS and alterations of LV hypertrophy and function. These beneficial effects on the heart were associated with the restoration of the cardiac insulin signaling pathway in MS rats.

Tangeretin mitigates l-NAME-induced ventricular dysfunction and remodeling through the AT1R/pERK1/2/pJNK signaling pathway in rats.

Tangeretin is a citrus flavonoid that exerts several beneficial effects, including anti-inflammation, anti-oxidation and neuroprotection. In this study, the aim was to test the effect of tangeretin on Nω-Nitro-l-arginine methyl ester (l-NAME)-induced high blood pressure, and left ventricular dysfunction and remodeling in rats. Rats were divided into five groups (n = 8 per each group): a control group, an l-NAME group and three l-NAME groups treated with tangeretin (15 mg kg-1) or tangeretin (30 mg kg-1) or captopril (5 mg kg-1) for the final two weeks. After five weeks of experiment, l-NAME groups had high systolic blood pressures, and ventricular dysfunction and remodeling. Overexpression of angiotensin II type 1 receptor, phosphorylated-extracellular-regulated kinase 1/2 (pERK1/2), and phosphorylated-c-Jun N-terminal kinase (pJNK) protein but downregulation of endothelial nitric oxide synthase (eNOS) protein expression in ventricular tissues were observed in hypertensive rats while the protein expression of phosphorylated-mitogen activated protein kinase p38 did not differ among groups. The decrease in plasma NOx and increase in vascular superoxide generation, plasma malondialdehyde, angiotensin-converting enzyme activity and angiotensin II levels were found in hypertensive rats. These alterations were suppressed in hypertensive rats treated with tangeretin or captopril. In conclusion, tangeretin exhibits antihypertensive effects and alleviates ventricular dysfunction and remodeling in hypertensive rats. These effects are associated with the inhibition of renin angiotensin system activation and restoration of pERK1/2, pJNK, and eNOS protein expressions along with reduced oxidative stress and increased NO bioavailability.