{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T12:28:57Z","timestamp":1789129737810,"version":"build-2803163510"},"reference-count":80,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"3","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2025,7,18]]},"abstract":"<jats:sec>\n            <jats:title>BACKGROUND:<\/jats:title>\n            <jats:p>\n              Calcineurin activity in the hypothalamic paraventricular nucleus (PVN) constitutively suppresses sympathetic output by tonically inhibiting glutamate NMDARs (\n              <jats:italic toggle=\"yes\">N<\/jats:italic>\n              -methyl-D-aspartate receptors). Clinically used calcineurin inhibitors diminish calcineurin activity in the PVN, leading to persistent overactivation of the sympathetic nervous system. In this study, we investigated the role of calcineurin signaling in the PVN in sympathetic overactivity in spontaneously hypertensive rats (SHR), a widely used genetic model for essential hypertension.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>METHODS:<\/jats:title>\n            <jats:p>Arterial blood pressure in conscious animals was recorded via radiotelemetry. Protein-protein interactions were assessed using coimmunoprecipitation, and synaptic NMDAR activity was measured using whole-cell patch-clamp recordings.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>RESULTS:<\/jats:title>\n            <jats:p>Calcineurin phosphatase activity in the PVN and other forebrain regions was much lower in SHR than in normotensive Wistar-Kyoto rats (WKY). However, systemic treatment with angiotensin II had no significant effect on brain calcineurin activity. Systemic administration of tacrolimus (FK506), a specific calcineurin inhibitor, induced persistent hypertension in WKY but did not affect the already elevated blood pressure in SHR. Also, microinjection of FK506 into the PVN significantly increased renal sympathetic nerve activity and blood pressure in WKY but had no effect on SHR. Furthermore, FK506 treatment increased \u03b12\u03b4-1\u2013NMDAR interactions and synaptic NMDAR activity in spinally projecting PVN neurons in WKY but not in SHR. Blocking NMDARs with memantine or inhibiting \u03b12\u03b4-1 with gabapentin substantially reduced elevated blood pressure in both FK506-treated WKY and SHR. Despite comparable levels of calcineurin-NMDAR complexes in the PVN of WKY and SHR, the interaction between calcineurin and RCAN1 (regulator of calcineurin 1, also known as calcipressin-1 or DSCR1 [Down syndrome critical region 1]), an endogenous calcineurin inhibitor, was significantly increased in SHR. Serine phosphorylation of RCAN1.1L in the PVN was much greater in SHR than in WKY. Disrupting RCAN1-calcineurin interactions using an RCAN1 C terminus peptide reversed synaptic NMDAR hyperactivity in spinally projecting PVN neurons in SHR. In addition, microinjection of the RCAN1 C terminus peptide into the PVN attenuated renal sympathetic nerve activity and arterial blood pressure in SHR.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>CONCLUSIONS:<\/jats:title>\n            <jats:p>RCAN1-mediated calcineurin hypoactivity in the PVN augments sympathetic outflow by promoting synaptic expression and activity of \u03b12\u03b4-1\u2013bound NMDARs in SHR. These findings identify a novel molecular mechanism underlying sympathetic overactivity in genetic hypertension and suggest potential therapeutic targets for neurogenic hypertension.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circresaha.124.325975","type":"journal-article","created":{"date-parts":[[2025,6,13]],"date-time":"2025-06-13T05:00:13Z","timestamp":1749790813000},"page":"417-434","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":10,"title":["RCAN1-Mediated Calcineurin Impairment Drives Sympathetic Outflow in Hypertension"],"prefix":"10.1161","volume":"137","author":[{"given":"Jing-Jing","family":"Zhou","sequence":"first","affiliation":[{"name":"Department of Anesthesiology and Perioperative Medicine, Center for Neuroscience and Pain Research, The University of Texas MD Anderson Cancer Center, Houston, 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