Interleukin 17A Contributes to Blood‐Brain Barrier Disruption of Hypothalamic Paraventricular Nucleus in Rats With Myocardial Infarction
Background Elevated inflammatory cytokines in the periphery have been identified as active contributors to neuroinflammation and sympathetic overactivity in heart failure (HF). Yet, the exact mechanisms by which these cytokines breach the blood‐brain barrier (BBB) to exert their effects on the brain...
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| Format: | Article |
| Language: | English |
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Wiley
2024-02-01
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| Series: | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| Subjects: | |
| Online Access: | https://www.ahajournals.org/doi/10.1161/JAHA.123.032533 |
| _version_ | 1827342060297912320 |
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| author | Yang Yu Robert M. Weiss Shun‐Guang Wei |
| author_facet | Yang Yu Robert M. Weiss Shun‐Guang Wei |
| author_sort | Yang Yu |
| collection | DOAJ |
| description | Background Elevated inflammatory cytokines in the periphery have been identified as active contributors to neuroinflammation and sympathetic overactivity in heart failure (HF). Yet, the exact mechanisms by which these cytokines breach the blood‐brain barrier (BBB) to exert their effects on the brain remain elusive. Interleukin 17A has been linked to BBB disruption in various neurologic disorders, and its levels were significantly augmented in circulation and the brain in HF. The present study aimed to determine whether the BBB integrity was compromised within the hypothalamic paraventricular nucleus (PVN), and if so, whether interleukin 17A contributes to BBB disruption in myocardial infarction–induced HF. Methods and Results Male Sprague‐Dawley rats underwent coronary artery ligation to induce HF or sham surgery. Some HF rats received bilateral PVN microinjections of an interleukin 17 receptor A small interfering RNA or a scrambled small interfering RNA adeno‐associated virus. Four weeks after coronary artery ligation, the permeability of the BBB was evaluated by intracarotid injection of fluorescent dyes (fluorescein isothiocyanate–dextran 10 kDa+rhodamine‐dextran 70 kDa). Compared with sham‐operated rats, HF rats exhibited an elevated extravasation of fluorescein isothiocyanate–dextran 10 kDa within the PVN but not in the brain cortex. The plasma interleukin 17A levels were positively correlated with fluorescein isothiocyanate 10 kDa extravasation in the PVN. The expression of caveolin‐1, a transcytosis marker, was augmented, whereas the expression of tight junction proteins was diminished in HF rats. Interleukin 17 receptor A was identified within the endothelium of PVN microvessels. Treatment with interleukin 17 receptor A small interfering RNA led to a significant attenuation of fluorescein isothiocyanate 10 kDa extravasation in the PVN and reversed expression of caveolin‐1 and tight junction–associated proteins in the PVN. Conclusions Collectively, these data indicate that BBB permeability within the PVN is enhanced in HF and is likely attributable to increased interleukin 17A/interleukin 17 receptor A signaling in the BBB endothelium, by promoting caveolar transcytosis and degradation of tight junction complexes. |
| first_indexed | 2024-03-07T22:02:11Z |
| format | Article |
| id | doaj.art-65f17e402dc14ec4a6024257f73f8833 |
| institution | Directory Open Access Journal |
| issn | 2047-9980 |
| language | English |
| last_indexed | 2024-03-07T22:02:11Z |
| publishDate | 2024-02-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| spelling | doaj.art-65f17e402dc14ec4a6024257f73f88332024-02-24T04:06:35ZengWileyJournal of the American Heart Association: Cardiovascular and Cerebrovascular Disease2047-99802024-02-0113310.1161/JAHA.123.032533Interleukin 17A Contributes to Blood‐Brain Barrier Disruption of Hypothalamic Paraventricular Nucleus in Rats With Myocardial InfarctionYang Yu0Robert M. Weiss1Shun‐Guang Wei2Department of Internal Medicine University of Iowa Carver College of Medicine Iowa City IADepartment of Internal Medicine University of Iowa Carver College of Medicine Iowa City IADepartment of Internal Medicine University of Iowa Carver College of Medicine Iowa City IABackground Elevated inflammatory cytokines in the periphery have been identified as active contributors to neuroinflammation and sympathetic overactivity in heart failure (HF). Yet, the exact mechanisms by which these cytokines breach the blood‐brain barrier (BBB) to exert their effects on the brain remain elusive. Interleukin 17A has been linked to BBB disruption in various neurologic disorders, and its levels were significantly augmented in circulation and the brain in HF. The present study aimed to determine whether the BBB integrity was compromised within the hypothalamic paraventricular nucleus (PVN), and if so, whether interleukin 17A contributes to BBB disruption in myocardial infarction–induced HF. Methods and Results Male Sprague‐Dawley rats underwent coronary artery ligation to induce HF or sham surgery. Some HF rats received bilateral PVN microinjections of an interleukin 17 receptor A small interfering RNA or a scrambled small interfering RNA adeno‐associated virus. Four weeks after coronary artery ligation, the permeability of the BBB was evaluated by intracarotid injection of fluorescent dyes (fluorescein isothiocyanate–dextran 10 kDa+rhodamine‐dextran 70 kDa). Compared with sham‐operated rats, HF rats exhibited an elevated extravasation of fluorescein isothiocyanate–dextran 10 kDa within the PVN but not in the brain cortex. The plasma interleukin 17A levels were positively correlated with fluorescein isothiocyanate 10 kDa extravasation in the PVN. The expression of caveolin‐1, a transcytosis marker, was augmented, whereas the expression of tight junction proteins was diminished in HF rats. Interleukin 17 receptor A was identified within the endothelium of PVN microvessels. Treatment with interleukin 17 receptor A small interfering RNA led to a significant attenuation of fluorescein isothiocyanate 10 kDa extravasation in the PVN and reversed expression of caveolin‐1 and tight junction–associated proteins in the PVN. Conclusions Collectively, these data indicate that BBB permeability within the PVN is enhanced in HF and is likely attributable to increased interleukin 17A/interleukin 17 receptor A signaling in the BBB endothelium, by promoting caveolar transcytosis and degradation of tight junction complexes.https://www.ahajournals.org/doi/10.1161/JAHA.123.032533blood‐brain barrier disruptioncaveolin‐1heart failureinflammationoccludintight junction |
| spellingShingle | Yang Yu Robert M. Weiss Shun‐Guang Wei Interleukin 17A Contributes to Blood‐Brain Barrier Disruption of Hypothalamic Paraventricular Nucleus in Rats With Myocardial Infarction Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease blood‐brain barrier disruption caveolin‐1 heart failure inflammation occludin tight junction |
| title | Interleukin 17A Contributes to Blood‐Brain Barrier Disruption of Hypothalamic Paraventricular Nucleus in Rats With Myocardial Infarction |
| title_full | Interleukin 17A Contributes to Blood‐Brain Barrier Disruption of Hypothalamic Paraventricular Nucleus in Rats With Myocardial Infarction |
| title_fullStr | Interleukin 17A Contributes to Blood‐Brain Barrier Disruption of Hypothalamic Paraventricular Nucleus in Rats With Myocardial Infarction |
| title_full_unstemmed | Interleukin 17A Contributes to Blood‐Brain Barrier Disruption of Hypothalamic Paraventricular Nucleus in Rats With Myocardial Infarction |
| title_short | Interleukin 17A Contributes to Blood‐Brain Barrier Disruption of Hypothalamic Paraventricular Nucleus in Rats With Myocardial Infarction |
| title_sort | interleukin 17a contributes to blood brain barrier disruption of hypothalamic paraventricular nucleus in rats with myocardial infarction |
| topic | blood‐brain barrier disruption caveolin‐1 heart failure inflammation occludin tight junction |
| url | https://www.ahajournals.org/doi/10.1161/JAHA.123.032533 |
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