The Synthetic Flavonoid Hidrosmin Improves Endothelial Dysfunction and Atherosclerotic Lesions in Diabetic Mice

• Published in: Antioxidants 2022-12, Vol.11 (12), p.2499
• Main Authors: Jiménez-Castilla, Luna, Opazo-Ríos, Lucas, Marin-Royo, Gema, Orejudo, Macarena, Rodrigues-Diez, Raquel, Ballesteros-Martínez, Constanza, Soto-Catalán, Manuel, Caro-Ordieres, Teresa, Artaiz, Inés, Suarez-Cortés, Tatiana, Zazpe, Arturo, Hernández, Gonzalo, Cortés, Marcelino, Tuñón, José, Briones, Ana M, Egido, Jesús, Gómez-Guerrero, Carmen
• Format: Article
• Language: English
• Subjects: Animal models; Aorta; Apolipoprotein E; Arteries; Arteriosclerosis; Atherogenesis; Atherosclerosis; Bioflavonoids; Cardiovascular disease; cardiovascular diseases; Cholesterol; Coronary vessels; Diabetes; Diabetes mellitus (non-insulin dependent); Drinking water; Dyslipidemia; endothelial dysfunction; Endothelium; Flavones; Flavonoids; Glucose; Health aspects; hidrosmin; Hyperglycemia; Hypertension; Inflammation; Laboratories; Leptin; Males; Metabolic disorders; Metabolites; Microvasculature; Nitric oxide; Nitric-oxide synthase; obesity; Oral administration; Oxidants; Oxidative stress; Pharmaceutical industry; Senescence; Smooth muscle; Streptozocin; Structure-function relationships; Vein & artery diseases
• ISSN: 2076-3921; 2076-3921
• DOI: 10.3390/antiox11122499

In diabetes, chronic hyperglycemia, dyslipidemia, inflammation and oxidative stress contribute to the progression of macro/microvascular complications. Recently, benefits of the use of flavonoids in these conditions have been established. This study investigates, in two different mouse models of diabetes, the vasculoprotective effects of the synthetic flavonoid hidrosmin on endothelial dysfunction and atherogenesis. In a type 2 diabetes model of leptin-receptor-deficient (db/db) mice, orally administered hidrosmin (600 mg/kg/day) for 16 weeks markedly improved vascular function in aorta and mesenteric arteries without affecting vascular structural properties, as assessed by wire and pressure myography. In streptozotocin-induced type 1 diabetic apolipoprotein E-deficient mice, hidrosmin treatment for 7 weeks reduced atherosclerotic plaque size and lipid content; increased markers of plaque stability; and decreased markers of inflammation, senescence and oxidative stress in aorta. Hidrosmin showed cardiovascular safety, as neither functional nor structural abnormalities were noted in diabetic hearts. Ex vivo, hidrosmin induced vascular relaxation that was blocked by nitric oxide synthase (NOS) inhibition. In vitro, hidrosmin stimulated endothelial NOS activity and NO production and downregulated hyperglycemia-induced inflammatory and oxidant genes in vascular smooth muscle cells. Our results highlight hidrosmin as a potential add-on therapy in the treatment of macrovascular complications of diabetes.