Angiotensin II type 1 receptor-activated caspase-3 through ras/mitogen-activated protein kinase/extracellular signal-regulated kinase in the rostral ventrolateral medulla is involved in sympathoexcitation in stroke-prone spontaneously hypertensive rats

Takuya Kishi, Yoshitaka Hirooka, Satomi Konno, Kiyohiro Ogawa, Kenji Sunagawa

Research output: Contribution to journalArticle

67 Citations (Scopus)

Abstract

In the rostral ventrolateral medulla (RVLM), angiotensin II-derived superoxide anions, which increase sympathetic nerve activity, induce a pressor response by activating the p38 mitogen-activated protein kinase (p38 MAPK) and extracellular signal-regulated kinase (ERK) pathway. The small G protein Ras mediates a caspase-3-dependent apoptotic pathway through p38 MAPK, ERK, and c-Jun N-terminal kinase. We hypothesized that angiotensin II type 1 receptors activate caspase-3 through the Ras/p38 MAPK/ERK/c-Jun N-terminal kinase pathway in the RVLM and that this pathway is involved in sympathoexcitation in stroke-prone spontaneously hypertensive rats (SHRSP), a model of human hypertension. The activities of Ras, p38 MAPK, ERK, and caspase-3 in the RVLM were significantly higher in SHRSP (14 to 16 weeks old) than in age-matched Wistar-Kyoto rats (WKY). The mitochondrial apoptotic proteins Bax and Bad in the RVLM were significantly increased in SHRSP compared with WKY. c-Jun N-terminal kinase activity did not differ between SHRSP and WKY. In SHRSP, intracerebroventricular infusion of a Ras inhibitor significantly reduced sympathetic nerve activity and improved baroreflex sensitivity, partially because of inhibition of the Ras/p38 MAPK/ERK, Bax, Bad, and caspase-3 pathway in the RVLM. Intracerebroventricular infusion of a caspase-3 inhibitor also inhibited sympathetic nerve activity and improved baroreflex sensitivity in SHRSP. Intracerebroventricular infusion of an angiotensin II type 1 receptor blocker in SHRSP partially inhibited the Ras/p38 MAPK/ERK, Bax, Bad, and caspase-3 pathway in the RVLM. These findings suggest that in SHRSP, angiotensin II type 1 receptor-activated caspase-3 acting through the Ras/p38 MAPK/ERK pathway in the RVLM might be involved in sympathoexcitation, which in turn plays a crucial role in the pathogenesis of hypertension.

Original languageEnglish
Pages (from-to)291-297
Number of pages7
JournalHypertension
Volume55
Issue number2
DOIs
Publication statusPublished - Feb 1 2010

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Angiotensin Type 1 Receptor
Extracellular Signal-Regulated MAP Kinases
p38 Mitogen-Activated Protein Kinases
Inbred SHR Rats
Mitogen-Activated Protein Kinases
Caspase 3
Stroke
Intraventricular Infusions
Inbred WKY Rats
JNK Mitogen-Activated Protein Kinases
Baroreflex
Mitogen-Activated Protein Kinase 6
Hypertension
Angiotensin II Type 1 Receptor Blockers
Caspase Inhibitors
Monomeric GTP-Binding Proteins
Mitochondrial Proteins
Superoxides
Angiotensin II

All Science Journal Classification (ASJC) codes

  • Internal Medicine

Cite this

Angiotensin II type 1 receptor-activated caspase-3 through ras/mitogen-activated protein kinase/extracellular signal-regulated kinase in the rostral ventrolateral medulla is involved in sympathoexcitation in stroke-prone spontaneously hypertensive rats. / Kishi, Takuya; Hirooka, Yoshitaka; Konno, Satomi; Ogawa, Kiyohiro; Sunagawa, Kenji.

In: Hypertension, Vol. 55, No. 2, 01.02.2010, p. 291-297.

Research output: Contribution to journalArticle

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