Natural genetic variation in Stim1 creates stroke in the spontaneously hypertensive rat

Abstract

Similar to humans, the risk of cerebrovascular disease in stroke-prone spontaneously hypertensive rats (SHR-A3/SHRSP) arises from naturally occurring genetic variation. In the present study, we show the involvement of genetic variation affecting the store-operated calcium signaling gene, Stim1, in the pathogenesis of stroke in SHR. Stim1 is a key lymphocyte activation signaling molecule and contains functional variation in SHR-A3 that diverges from stroke-resistant SHR-B2. We created a SHR-A3 congenic line in which Stim1 was substituted with the corresponding genomic segment from SHR-B2. Compared with SHR-A3 rats, Stim1 congenic SHR-A3 (SHR-A3(Stim1-B2)) have reduced cerebrovascular disease in response to salt loading including lower neurological deficit scores and cerebral edema. Microbleeds and major hemorrhages occurred in over half of SHR-A3 rats. These lesions were absent in SHR-A3(Stim1-B2) rats. Loss of Stim1 function in mice and humans is associated with antibody-mediated autoimmunity due to defects in T lymphocyte helper function to B cells. We investigated autoantibody formation using a high-density protein array to detect the presence of IgG and IgM autoantibodies in SHR-A3. Autoantibodies to key cerebrovascular stress proteins were detected that were reduced in the congenic line.

Genotypes of Stim1 and the proximal region on chromosome 1 exert opposite effects on stroke susceptibility in stroke-prone spontaneously hypertensive rat

“…(b) Macroscopic appearance of the brain with injury score grades 1–4; grade 1: no apparent lesions, 2: a single hemorrhage lesion without global edema, 3: hemorrhagic lesions and/or global edema, and 4; severe global edema with hemorrhagic lesions and cystic lesions. Solid arrows, dashed arrows, and arrowheads indicate hemorrhagic lesions, cystic lesions, and global cerebral edema (filling in of major brain sulci [12]), respectively. (c) Comparison of injury scores between Stim1 -KI SHRSP and the original SHRSP.…”

“…The role of STIM1 in the pathogenesis or prognosis of cerebrocardiovascular diseases in humans remains unclear. Although a high expression level of platelet STIM1 was previously reported to be associated with a poor prognosis in patients with ischemic stroke [40], this phenotype appeared to be the opposite to the reduction in SOCE activity in SHRSP [7,12,28]. The deletion of Stim1 in humans has been shown to induce rare hereditary diseases with immunological deficiencies [41,42]; however, there is currently no information on the clinical significance of a partial reduction in SOCE in humans.…”

“…Secondo et al [27] reported that a noninvasive MCAO treatment (called ischemic preconditioning; IPC) up-regulated the neuronal expression of STIM1 and ORAI1, two major components of SOCE, resulting in ischemic tolerance in neurons by restoring Ca 2þ homeostasis in the endoplasmic reticulum. As impaired SOCE activity has been ubiquitously observed in various types of cells in SHRSP [7,12,28], impaired neuronal ischemic tolerance may be responsible for the genetic predisposition of SHRSP to stroke. Further studies are required to verify this possibility.…”

“…As SOCE has been reported to play important roles in the regulation of intracellular Ca 2þ dynamics in many nonexcitatory cells, such as endothelial cells and lymphocytes [9][10][11], we hypothesized that the nonsense mutation in Stim1, which was specific to SHRSP [6], may affect stroke susceptibility in SHRSP. A previous study indicated that stroke susceptibility under salt loading was significantly higher in SHR-A3 (a substrain of SHRSP having the same nonsense mutation of Stim1) than in congenic SHR-A3 with the wild-type Stim1 introgressed from stroke-resistant SHR-A2 [12]. Although these findings suggested that Stim1 was responsible for high stroke susceptibility in SHR-A3, it was not conclusive because the congenic SHR-A3 used in that study had a 45-Mb fragment from SHR-A2, which contained many genes in addition to Stim1.…”

Translational Stroke Research Review: Using the Mouse to Model Human Futile Recanalization and Reperfusion Injury in Ischemic Brain Tissue

“…Nevertheless, preclinical research makes great efforts to develop animal models that better resemble the multifaceted scenario of stroke patients by exploiting aging animals [ 74 , 75 , 76 ], genetically modified animal lines [ 77 , 78 , 79 , 80 ], and novel fine-tuned experimental protocols to overcome the complications of some procedures [ 64 , 71 , 79 ].…”