Abstract 4891: Angiotensin II-activated Caspase 3-dependent Apoptosis in the RVLM Contributes to Sympathoexcitaion Through the Activation of Ras/MAPK/ERK Pathway
Background: The rostal ventrolateral medulla (RVLM) regulates sympathetic nerve activity (SNA). Angiotensin II-derived superoxide anion in the RVLM induces the pressor response via the activation of p38 mitogen-activated protein kinase (p38 MAPK) and extracellular signal-regulated kinase (ERK). Small G protein Ras mediates caspase 3-dependent apoptosis through the activation of p38 MAPK and ERK. We hypothesized that angiotensin II/angiotensin II type 1 receptor (AT1R)-activated caspase 3-dependent apoptosis in the RVLM contributes to sympathoexcitation through the activation of Ras/p38 MAPK/ERK pathway in stroke-prone spontaneously hypertensive rats (SHRSP).
Methods and Results: Telemetrically measured mean blood pressure (MBP) and heart rate (HR) under a conscious state, and SNA assessed by urinary norepinephrine excretion, were significantly higher in SHRSP than in Wistar-Kyoto (WKY) rats. Activities of Ras, p38 MAPK, ERK, and caspase 3 in the RVLM were significantly higher in SHRSP than in WKY (Ras; 1.7 ± 0.2 U vs 1.3 ± 0.2 U, p38 MAPK; 1.8 ± 0.1 U vs 1.2 ± 0.3 U, ERK; 2.1 ± 0.3 U vs 1.4 ± 0.3 U, caspase 3; 1.7 ± 0.1 U vs 1.1 ± 0.2 U, n = 5 for each, P < 0.01). Mitochondrial apoptotic proteins Bax and Bad in the RVLM were also significantly increased in SHRSP (Bax; + 38 ± 2%, Bad; + 43 ± 3%, n = 5 for each, P < 0.01). In SHRSP, intracerebroventricular (ICV) infusion of Ras inhibitor, Z-DEVD-FMK, significantly reduced MBP, HR, and SNA (MBP; −38 ± 4mmHg, HR; −44 ± 18bpm, SNA; −0.8 ± 0.2 μ g/day, n = 5 for each, P < 0.01) and inhibited activities of Ras/p38 MAPK/ERK, Bax, Bad, and caspase 3 in the RVLM (Ras; −36 ± 3%, p38 MAPK; −27 ± 3%, ERK; −24 ± 2%, Bax; −21 ± 3%, Bad; −28 ± 5%, caspase 3; −39 ± 6%, n = 5 for each, P < 0.01). ICV of caspase 3 inhibitor also decreased MBP, HR, and SNA in SHRSP. ICV of AT1R blocker, candesartan, in SHRSP decreased MBP, HR, and SNA (MBP; −34 ± 5mmHg, HR; −52 ± 14bpm, SNA; −0.9 ± 0.2 μ g/day, n = 5 for each, P < 0.01) and reduced activities of Ras/p38 MAPK/ERK, Bax, Bad, and caspase 3 in the RVLM.
Conclusion: Angiotensin II/AT1R-activated caspase 3-dependent apoptosis in the RVLM increases SNA through the activation of Ras/p38 MAPK/ERK pathway in SHRSP. This mechanism of sympathoexcitation may play a crucial role in the pathogenesis of hypertension.