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.

Clitoria ternatea (Linn.) flower extract attenuates vascular dysfunction and cardiac hypertrophy via modulation of Ang II/AT1 R/TGF-ß1 cascade in hypertensive rats.

BACKGROUND: Clitoria ternatea (CT) (the Fabaceae family) has been reported to elicit several biological responses, such as anti-inflammation and anti-depression effects. This study evaluated the effect of CT flower extract on blood pressure, vascular function, and left ventricular hypertrophy in a two-kidney, one-clip (2K-1C) rat model. Hypertensive rats were treated with CT extract at various doses (100, 300, or 500 mg kg-1 day-1 ) or losartan (10 mg kg-1 day-1 ) for 4 weeks (n = 8/group). RESULTS: CT extract reduced blood pressure in a dose-dependent manner, and CT extract at a dose of 300 mg kg-1 was an effective concentration (P < 0.05). Augmentation of contractile responses to electrical field stimulation and impairment of vascular responses to acetylcholine in mesenteric vascular beds and aortic rings of 2K-1C rats were suppressed by treatment with CT extract or losartan (P < 0.05). Serum angiotensin-converting enzyme activity and plasma angiotensin II concentration were high in 2K-1C rats but alleviated by CT extract or losartan treatment (P < 0.05). Increases in superoxide production and lipid peroxidation were attenuated in 2K-1C rats treated with CT extract or losartan compared with the untreated group (P < 0.05). Increased plasma concentration of nitric oxide metabolites was found in hypertensive rats that received CT extract or losartan. CT extract or losartan suppressed the overexpression of Ang II receptor subtype I (AT1 -R) and transforming growth factor-ß1 (TGF-ß1) in 2K-1C rats. CONCLUSION: CT extract had antihypertensive effects that were associated with improving vascular function and cardiac hypertrophy in 2K-1C rats. The mechanisms involved suppression of the renin-angiotensin system, of oxidative stress, and of the AT1 R/TGF-ß1 cascade. © 2021 Society of Chemical Industry.

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.

Nobiletin alleviates vascular alterations through modulation of Nrf-2/HO-1 and MMP pathways in l-NAME induced hypertensive rats.

Nobiletin, a citrus flavonoid, exhibits a wide range of biological activities. This study investigated the effect of nobiletin on vascular dysfunction and remodeling in l-NAME-induced hypertensive rats. Male Sprague-Dawley rats were given l-NAME (40 mg kg-1) for five weeks to induce hypertension and treated with nobiletin (20 or 40 mg kg-1) or captopril (5 mg kg-1) for the last two weeks. Nobiletin or captopril significantly reduced blood pressure and the enhancement of the contractile response to sympathetic nerve stimulation in the mesenteric vascular beds of l-NAME rats (p < 0.05). Both agents improved the impairment of vasorelaxation responses to acetylcholine in mesenteric vascular beds and aortic rings in l-NAME rats (p < 0.05). Moreover, nobiletin and captopril decreased oxidative stress markers, restored the abnormality of plasma NOx and the protein expressions of eNOS, Nrf-2 and HO-1 observed in l-NAME rats (p < 0.05). Increases in aortic wall thickness, cross sectional area, vascular smooth muscle cells and collagen deposition that occurred in l-NAME rats were reduced by nobiletin or captopril (p < 0.05). These reductions were associated with the suppression of matrix metalloproteinase (MMP)-2 and MMP-9 protein expression (p < 0.05). These findings indicated that nobiletin had antihypertensive effects with amelioration of vascular alterations. The molecular mechanism is likely to involve the restoration of Nrf-2/HO-1/MMP signaling pathways.

Hesperidin Suppresses Renin-Angiotensin System Mediated NOX2 Over-Expression and Sympathoexcitation in 2K-1C Hypertensive Rats.

Hesperidin, a flavonoid derived from citrus fruits, possesses several beneficial effects including anti-oxidation and anti-inflammation. The aim of this study was to investigate the effects of hesperidin on the renin-angiotensin system (RAS) cascade that mediated oxidative stress and sympathoexcitation in two-kidney, one-clipped (2K-1C) hypertensive rats. 2K-1C hypertension was induced in male Sprague-Dawley rats. Hypertensive rats were treated with hesperidin at 20[Formula: see text]mg/kg or 40[Formula: see text]mg/kg or losartan at 10[Formula: see text]mg/kg beginning at three weeks after surgery and then continued for four weeks ([Formula: see text]/group). Hesperidin reduced blood pressure in a dose-dependent manner in hypertensive rats compared to untreated rats ([Formula: see text]). Increased plasma angiotensin converting enzyme (ACE) activity and angiotensin II levels, as well as, upregulated AT1 receptor protein expression in aortic tissues were attenuated in hypertensive rats treated with hesperidin. Hesperidin suppressed oxidative stress markers and NADPH oxidase over-expression, and restored plasma nitric oxide metabolites in 2K-1C rats. This was associated with improvement of the vascular response to acetylcholine in isolated mesenteric vascular beds and aortic rings from 2K-1C rats treated with hesperidin ([Formula: see text]). Enhancement of nerve-mediated vasoconstriction related to high plasma noradrenaline in the 2K-1C group was alleviated by hesperidin treatment ([Formula: see text]). Furthermore, losartan exhibited antihypertensive effects by suppressing the RAS cascade and oxidative stress and improved vascular dysfunction observed in 2K-1C rats ([Formula: see text]). Based on these results, it can be presumed that hesperidin is an antihypertensive agent. Its antihypertensive action might be associated with reducing RAS cascade-induced NOX2 over-expression and sympathoexcitation in 2K-1C hypertensive rats.

Carthamus tinctorius L. extract improves hemodynamic and vascular alterations in a rat model of renovascular hypertension through Ang II-AT1R-NADPH oxidase pathway.

Carthamus tinctorius L. (CT) is widely used in Asian countries as a beverage and in folk medicine. The effects of CT extract on hemodynamics, vascular remodeling, the renin-angiotensin system (RAS) and oxidative stress in the two-kidney, one clip (2K-1C) hypertensive rat model were investigated. Renovascular hypertension was induced in male Sprague-Dawley rats and were treated with CT extract (500mg/kg/day) or captopril (5mg/kg/day) or vehicle for four weeks. CT extract or captopril reduced blood pressure, hindlimb vascular resistance, and increased hindlimb blood flow in 2K-1C hypertensive rats (p<0.05). Increases in aortic wall thickness, cross-sectional area and collagen deposition in 2K-1C rats were alleviated with CT extract or captopril treatment (p<0.05). CT extract or captopril suppressed RAS activation, including elevated serum ACE activity, and plasma Ang II level and up-regulated aortic AT1R protein expression in 2K-1C rats (p<0.05). Furthermore, CT extract or captopril reduced vascular superoxide production, aortic NADPH oxidase subunit gp91phox expression and increased plasma nitric oxide metabolite levels in 2K-1C rats (p<0.05). These findings suggest that CT extract ameliorated hemodynamic alteration and vascular remodeling in 2K-1C hypertensive rats. Possible mechanisms may involve RAS inhibitor effects and potent antioxidant activity.