Myocardial infarction-induced disruption of blood-brain barrier in hypothalamic paraventricular nucleus is mediated by interleukin-17A signaling in rat

Increased inflammatory cytokines in the circulation act in the brain to promote neuroinflammation and sympathetic excitation in myocardial infarction-induced heart failure (HF). However, the mechanisms by which proinflammatory cytokines interrupt blood-brain barrier (BBB) to reach brain remain unclear. We recently reported that the levels of interleukin (IL)-17A, a key inflammatory mediator of immune responses, are significantly elevated in circulation and the brain in HF. IL-17A has been shown to disrupt the integrity of BBB in in vitro model and in vivo rodent model of experimental autoimmune encephalomyelitis. The present study sought to determine whether BBB in hypothalamic paraventricular nucleus (PVN), a key cardiovascular/autonomic region of the brain within the BBB, was damaged in HF and if so, whether IL-17A contributes to BBB disruption in this disease setting. Adult male Sprague Dawley rats underwent coronary artery ligation to induce HF or sham surgery (Sham). Some HF rats were pretreated with bilateral PVN microinjections of an IL-17 receptor A (IL-17RA) siRNA AAV virus or a scrambled siRNA control. The left ventricular function and infarction size were evaluated by echocardiography. Four weeks after coronary artery ligation, BBB permeability was assessed with fluorescein isothiocyanate (FITC, 10 kDa)-dextran extravasation and molecular measurements of its biomarkers. FITC was injected through left carotid artery at a rate of 300 μl/min (10 mg/ml, 3 ml/kg) and allowed to circulate for 30 min. We found that HF rats displayed noticeable FITC extravasation within the PVN area when compared with brain cortex after injections. FITC extravasation was not observed in the PVN and brain cortex in Sham rats. Compared with Sham rats, HF rats had significantly increased PVN mRNA expression of caveolin-1 (1.05± 0.13 vs 3.30 ± 0.48*, fold changes; *P<0.05), a molecular marker of transcytosis, and decreased PVN mRNA levels of occludin and zonula occludens-1 (1.05± 0.14 vs 0.57 ± 0.13*; 1.05± 0.10 vs 0.54 ± 0.03*, respectively), two important tight junction-associated molecules. However, the mRNA expression of caveolin-1, occludin or zonula occludens-1 did not display significant difference in the brain cortex between HF and Sham rats. Pretreatment with IL-17RA siRNA, substantially reduced FITC extravasation within the PVN and reversed mRNA expression of caveolin-1 (1.08 ± 0.20 vs. 0.51 ± 0.09*), occludin (1.07 ± 0.15 vs. 1.86 ± 0.18*) or zonula occludens-1 (1.02 ± 0.08 vs.1.84 ± 0.24*) in HF rats when compared with HF rats pretreated with a scrambled siRNA control. These data indicated that BBB permeability is increased in the PVN in myocardial infarction-induced HF. The activated IL-17A/IL-17RA signaling in BBB endothelium in the PVN in HF may play an important role in disrupting BBB, probably by a molecular mechanism to augment transcellular transport and reduce tight junction protein expression. Supported by NIH grants R01 HL-139521 & HL-155091 to SGW This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.