Abstract 028: Susceptibility to Strokes in Spontaneously Hypertensive Rats Due to a Mutation in Stim1

Abstract

Stroke-prone spontaneously hypertensive rats (SHR-A3/SHRSP) develop cerebrovascular disease as a result of naturally occurring genetic variation. We recently identified a novel truncating mutation in the SHR-A3 line affecting the C-terminus of STIM1, a protein involved in the store-operated Ca 2+ entry (SOCE) pathway. The SHR-B2 line, which is also hypertensive but resists end organ injury, expresses the ‘wild type’ Stim1 . Here, we test whether the emergence of cerebrovascular disease in SHR-A3 is prevented by gene rescue of Stim1 . We created a Stim1 congenic line (SHR-A3( Stim1 -B2)), in which the functional Stim1 allele was transferred from the SHR-B2 line into the stroke-prone SHR-A3 genome. SHR-A3 and SHR-A3( Stim1 -B2) rats were salt loaded (1% NaCl in drinking water) for 8 weeks starting at 20 weeks of age to induce strokes. Baseline BP measured by telemetry before salt loading was not different between SHR-A3 and SHR-A3( Stim1 -B2) rats (199.5±6.49 vs 196.26±2.431 mmHg, ns). Salt loading resulted in a progressive increase in BP in SHR-A3 rats, but was blunted in SHR-A3( Stim1 -B2) rats. Compared to SHR-A3 rats, Stim1 -rescue congenic rats had improved survival (% survival: 100 (9 of 9) vs 22.2% (2 of 9) at the end of 8 weeks) and lower neurological deficit scores (2.45±0.412 vs 1±0.00, p<0.01). Salt loading resulted in significant cerebral edema in SHR-A3 rats but not in the SHR-A3( Stim1 -B2) rats (% brain wt/body wt: 0.805±0.045 vs 0.617±0.009, p<0.01). Gross morphology of the brain revealed microbleeds and hemorrhages in 5 of 9 SHR-A3 rats. These lesions were absent in SHR-A3( Stim1 -B2) rats. Stim1 gene rescue in the congenic line was also associated with decreased susceptibility to renal injury assessed histologically at 40 weeks of age (glomerular injury: 1.915±0.086 vs 1.355±0.071, p<0.001; tubulointerstitial injury: 3.2±0.102 vs 1.69±0.112, p<0.001). Our findings identify Stim1 as a major candidate gene that promotes susceptibility to strokes as well as renal injury in spontaneously hypertensive rats.