Moxonidine ameliorates cardiac injury in rats with metabolic syndrome by regulating autophagy

• Published in: Life sciences (1973) Vol. 312; p. 121210
• Main Authors: El-Sayed, Shaimaa S., Rezq, Samar, Alsemeh, Amira Ebrahim, Mahmoud, Mona F.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 01.01.2023
• Subjects: Animals; Apoptosis; Autophagy; Beclin-1 - metabolism; Heart; Imidazoline Receptors - metabolism; Imidazoline-1 receptor; Metabolic syndrome; Metabolic Syndrome - complications; Metabolic Syndrome - drug therapy; Metabolic Syndrome - metabolism; NR4A2; Rats; Sequestosome-1 Protein - metabolism; Tumor Suppressor Protein p53; Heart; LDL-C; RAAS; ALT; LV; I1R; MDA; WC; Metabolic syndrome; c-TnI; Autophagy; HDL-C; DBP; BMI; SBP; AST; BGL; AI; IL-6; TC; NR4A2; HOMA-IR; MetS; TG; TNF-α; TGF-β1; Imidazoline-1 receptor; OGTT; MAP; MMP-9; Apoptosis
• ISSN: 0024-3205; 1879-0631
• DOI: 10.1016/j.lfs.2022.121210

Reduced cardiac autophagy, ischemic injury, sympathetic overactivity, and apoptosis all contribute to metabolic syndrome (MetS)-associated cardiovascular risks. NR4A2, an orphan nuclear receptor NR4A family member, induces autophagy while suppressing apoptosis in myocardial infarction. Moxonidine, a sympathoinhibitor imidazoline1 receptor (I1R) agonist, has beneficial metabolic and hemodynamic effects; however, whether autophagy and/or NR4A2 signaling are involved in moxonidine's cardiovascular effects via I1R activation, is unknown, and is the aim of this study. To induce MetS, rats were fed 3 % salt in their diet and 10 % fructose in their drinking water for 12 weeks. MetS-rats were given either moxonidine (6 mg/kg/day, gavage), efaroxan (I1R antagonist, 0.6 mg/kg/day, i.p), both treatments, or vehicles for the last two weeks. Blood pressure, lipid profile, and glycemic control were evaluated. Histopathological examination, circulating cardiac troponin I (c-TnI), proinflammatory interleukin-6 (IL-6), apoptosis (active caspase-3 and Fas-immunostaining), interstitial fibrosis [transforming growth factor-β1 (TGF-β1), Mallory's trichrome staining], and extracellular matrix remodeling [matrix metalloproteinase-9 (MMP-9)], were used to assess cardiac pathology. Cardiac NR4A2 and its downstream factor, p53, as well as autophagic flux markers, SQSTM1/p62, LC3, and Beclin-1 were also determined. Moxonidine significantly ameliorated MetS-induced metabolic and hemodynamic derangements and the associated cardiac pathology. Moxonidine restored NR4A2 and p53 myocardial levels and enhanced autophagic flux via modulating SQSTM1/p62, LC3, and Beclin-1. Efaroxan reversed the majority of the moxonidine-induced improvements. The current study suggests that autophagy modulation via I1R activation is involved in moxonidine-mediated cardiac beneficial effects in MetS. [Display omitted]