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Published on: June 10, 2015
Congenic substitution mapping for intracellular Ca2+ in spontaneously hypertensive rats
Yoichi Ohno1, Yosuke Ando, Tatsuya Maruyama
1Department of Internal Medicine, Saitama Municipal Hospital, Saitama, Japan. yo1-ohno@jocom.home.ne.jp
Insights
A specific gene region on chromosome 12, near the Serca II gene, was found to influence intracellular calcium levels and platelet aggregation. This region is linked to reduced hypertension and cardiac hypertrophy in rats, suggesting a role in cardiovascular health.
Area of Science:
- Cardiovascular Research
- Genetics
- Physiology
Background:
- Intracellular calcium ([Ca(2+)](i)) plays a role in hypertension and platelet hyperactivity in spontaneously hypertensive rats (SHR).
- A quantitative trait locus (QTL) for platelet [Ca(2+)](i) was identified near the sarco(endo)plasmic reticulum Ca(2+)-dependent ATPase (Serca) II gene locus on chromosome 12.
Purpose of the Study:
- To investigate the role of the Serca II gene locus region in hypertension and platelet function in SHR.
- To determine if a specific chromosomal segment influences intracellular calcium regulation and cardiovascular parameters.
Main Methods:
- Congenic substitution mapping was employed to transfer a chromosomal segment containing the Serca II gene locus from Fischer 344 (F344) rats to the SHR genetic background.
- Systolic blood pressure (SBP), platelet aggregation, heart weight to body weight ratio (HW/BW), and platelet [Ca(2+)](i) responses were compared between SHR and the congenic strain.
Main Results:
- SHR exhibited significantly higher platelet [Ca(2+)](i), platelet aggregation, SBP, and HW/BW compared to F344 rats.
- Heterozygous congenic rats with the transferred segment showed attenuated [Ca(2+)](i) responses and platelet aggregation.
- These congenic rats also demonstrated significantly lower SBP and HW/BW.
Conclusions:
- A chromosomal segment encompassing the Serca II gene locus is responsible for attenuated [Ca(2+)](i) responses and platelet aggregation.
- This chromosomal region may contribute to the development of hypertension and cardiac hypertrophy in SHR by modulating calcium signaling.
Background:
Intracellular Ca(2+) ([Ca(2+)](i)) may be a factor of importance to hypertension in spontaneously hypertensive rats (SHR). Platelet hyperactivity caused by increased [Ca(2+)](i) may contribute to atherothrombotic cardiovascular events. In a genome scan, we have recently demonstrated that a candidate quantitative trait locus (QTL) for [Ca(2+)](i) in platelets is located near the sarco(endo)plasmic reticulum Ca(2+)-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 [Ca(2+)](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 [Ca(2+)](i) in platelets, platelet aggregation, SBP, and HW/BW were significantly greater in SHR than in F344 and F(1) rats. The heterozygous congenic rats for the Serca II gene segment had significantly attenuated [Ca(2+)](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 [Ca(2+)](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 Ca(2+) signaling in SHR.
