Diosmin Prevents L-NAME-Induced Vascular Dysfunction and Remodeling in Rats via Suppressing the TGF-β1 Downstream Signaling Pathway

Abstract

Background: Diosmin is a flavanone glycoside found in several citrus fruits’ pericarps, presenting several biological effects. The current research examined the effects and potential mechanisms of diosmin on vascular abnormalities in Sprague Dawley rats administered N^ω-nitro-L-arginine methyl ester (L-NAME) hydrochloride, an L-arginine analog. A total of 40 rats were randomly assigned into five groups (n = 8 per group): control, L-NAME, L-NAME + low-dose diosmin, L-NAME + high-dose diosmin, and L-NAME + azilsartan. Treatments were given orally for 5 weeks.

Results: Diosmin mitigated high blood pressure in rats exposed to a nitric oxide synthase inhibitor (p < 0.05). Vascular dysfunction caused by nitric oxide deficiency in both conduit and small arteries was alleviated by diosmin. Vascular remodeling included augmentations in aortic hypertrophy, number of vascular smooth muscle cells (VSMCs), and fibrosis accumulation, which were improved by diosmin management (p < 0.05). Diosmin restored phosphorylated nitric oxide synthase 3 (p-NOS3) protein expression, enhanced circulating nitrite/nitrate production, upregulated antioxidant defense enzymes, normalized the elevations of malondialdehyde (MDA) level, and suppressed renin–angiotensin system (RAS) overactivity (p < 0.05). Upregulation of aortic protein expression relevant to a hypertrophic pathway; angiotensin II receptor Type I (AT1R), gp91^phox, transforming growth factor-beta 1 (TGF-β1), Janus kinase 2 (JAK2), signal transducer and activator of transcription 3 (STAT3), and matrix metalloproteinase-2 (MMP-2) proteins in rats given L-NAME were suppressed by diosmin (p < 0.05). Azilsartan was utilized as a positive control, demonstrating effects comparable to those observed with diosmin.

Conclusion: These data suggested that diosmin exerts vasoprotective capacity in an animal model of hypertension. The possible mechanism was by inhibiting RAS activation and suppressing TGF-β1, JAK2, STAT3, and MMP-2 protein expressions, in accordance with decreasing oxidative stress and raising NO bioavailability.