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Ras‐activated caspase 3‐dependent apoptosis through MAPK and p53 in RVLM increases sympathetic nerve activity in SHRSP
Author(s) -
Kishi Takuya,
Hirooka Yoshitaka,
Ito Koji,
Araki Shuichiro,
Konno Satomi,
Sunagawa Kenji
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.958.8
Subject(s) - rostral ventrolateral medulla , mapk/erk pathway , medicine , endocrinology , angiotensin ii , apoptosis , renin–angiotensin system , chemistry , protein kinase a , kinase , caspase 3 , blood pressure , heart rate , programmed cell death , biochemistry
Background The small G protein Ras causes caspase‐3 dependent apoptosis through mitogen‐activated protein kinase (MAPK), extracellular signal‐regulated kinase (ERK) and p53. Angiotensin II administered into the rostral ventrolateral medulla (RVLM) induces pressor response through the activation of p38 MAPK and ERK. We hypothesized that Ras‐activated caspase‐3 through MAPK/ERK/p53 in RVLM increases SNA in stroke‐prone spontaneously hypertensive rats (SHRSP), Methods and Results Activity of Ras, MAPK, ERK and caspase‐3 and expression of p53 in RVLM were significantly higher in SHRSP (14‐16 weeks old) than in age‐matched Wistar‐Kyoto (WKY) rats. In SHRSP, intracerebroventricular (ICV) infusion of S‐farnesylthiosalicylic acid, a Ras inhibitor, for 14 days significantly reduced blood pressure (BP), heart rate (HR) (‐28±4 mmHg and ‐44±6 bpm, n=5, p<0.01) and SNA (‐28%, n=5, p<0.01) due to the inhibition of Ras activity in RVLM. A Ras inhibitor decreased the activity of MAPK (‐21%, n=5, p<0.01), ERK (‐33%, n=5, p<0.01), caspase‐3 (‐42%, n=5, p<0.01) and expression of p53 in RVLM of SHRSP. ICV injection of caspase‐3 inhibitor for 14 days also significantly decreased BP, HR, SNA and activity of caspase‐3 in RVLM. Conclusion These results suggest that Ras‐activated caspase‐3 through MAPK and p53 in RVLM increases SNA in SHRSP, which might contribute to the impaired autonomic control in hypertension.