Congenic Substitution Mapping for Intracellular Ca2+ in Spontaneously Hypertensive Rats

Background Intracellular Ca2+ ([Ca2+]i) may be a factor of importance to hypertension in spontaneously hypertensive rats (SHR). Platelet hyperactivity caused by increased [Ca2+]i may contribute to atherothrombotic cardiovascular events. In a genome scan, we have recently demonstrated that a candidate quantitative trait locus (QTL) for [Ca2+]i in platelets is located near the sarco(endo)plasmic reticulum Ca2+-dependent ATPase (Serca) II gene locus on chromosome 12 in backcrossed rats derived from SHR and normotensive Fischer 344 rats (F344). Methods Congenic substitution mapping was performed for the chromosomal region including the Serca II gene locus. The segment including the Serca II gene locus was transferred from F344 onto the genetic background of the progenitor SHR. Systolic blood pressure (SBP), platelet aggregation, and ratio of heart weight to body weight (HW/BW) as well as [Ca2+]i responses in platelets were compared between SHR and the congenic strain. Results Among the parental strains, thrombin-stimulated and thapsigargin-induced peak values of [Ca2+]i in platelets, platelet aggregation, SBP, and HW/BW were significantly greater in SHR than in F344 and F1 rats. The heterozygous congenic rats for the Serca II gene segment had significantly attenuated [Ca2+]i responses and platelet aggregation compared with SHR. Furthermore, they demonstrated significantly lower SBP and HW/BW. Conclusion Congenic substitution mapping clarified that a chromosomal segment including the Serca II gene locus was responsible for attenuated [Ca2+]i responses and platelet aggregation in the heterozygous congenic rats. Therefore, this chromosomal region may contribute to the development of hypertension and cardiac hypertrophy by augmenting Ca2+ signaling in SHR.