Dimethyl Fumarate Prevents the Development of Chronic Social Stress-Induced Hypertension in Borderline Hypertensive Rats

• Main Authors: Michal Kluknavsky (Author), Peter Balis (Author), Silvia Liskova (Author), Andrea Micurova (Author), Martin Skratek (Author), Jan Manka (Author), Iveta Bernatova (Author)
• Format: Book
• Published: MDPI AG, 2024-08-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.
• Notes: 10.3390/antiox13080947; 2076-3921
• Keywords: NRF2; <i>Nfe2l2</i>; chronic stress; cardiovascular function; Therapeutics. Pharmacology; RM1-950
• Source: Antioxidants, Vol 13, Iss 8, p 947 (2024)

This study investigated the effects of chronic crowding-induced social stress and dimethyl fumarate (DMF) on borderline hypertensive rats, focusing on the transcription nuclear factor (erythroid-derived 2)-like 2 (NRF2) gene <i>Nfe2l2</i>, on the expression of selected NFR2-mediated gene expressions in the heart, and on vascular function. Rats were exposed to chronic crowding, DMF treatment (30 mg/kg/day, p.o.), or a combination of both for six weeks. Blood pressure (BP) was measured non-invasively, gene expressions were analysed using RT-qPCR, and vascular function was assessed by measuring noradrenaline (NA)-induced vasoconstriction and endothelium-dependent and -independent relaxations in the femoral arteries using a wire myograph. Chronic stress increased BP, <i>Nfe2l2</i> expression, and NA-induced vasoconstriction, though it did not affect relaxation responses nor the left heart ventricle-to-body weight (LHV/BW) ratio. DMF elevated <i>Nfe2l2</i> expression (as the main effect) in the heart but did not alter BP and vascular functions vs. control when administered alone. Interestingly, DMF increased the LHV/BW ratio, supposedly due to reductive stress induced by continuous NRF2 activation. When combined with stress, DMF treatment prevented stress-induced hypertension and mitigated NA-induced vasoconstriction without altering relaxation functions. In addition, the combination of stress and DMF increased <i>Tnf</i> and <i>Nos2</i> expression and the expressions of several genes involved in iron metabolism. In conclusion, these findings suggest that DMF can prevent chronic stress-induced hypertension by reducing vascular contractility. Moreover, DMF itself may produce reductive stress in the heart and induce inflammation when combined with stress. This indicates a need for the careful consideration of long-term DMF treatment considering its impact on the heart.