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Critical role for p47phox in renin-angiotensin system activation and blood pressure regulation.
Cardiovasc Res. 2006 Aug 01; 71(3):596-605.CR

Abstract

OBJECTIVE

Renin-angiotensin system (RAS) activation leads to increased production of NAD(P)H oxidase-derived reactive oxygen species (ROS), and both have been implicated in the initiation and progression of arterial hypertension, atherosclerosis, and cardiac hypertrophy. The cytosolic subunit p47phox is critically involved in agonist-induced NAD(P)H oxidase activation. Here, we investigated the role of p47phox in blood pressure control, endothelium-dependent relaxation, cardiac hypertrophy, RAS activation, and renal oxidative stress under resting conditions.

METHODS AND RESULTS

Mice deficient in p47phox (on C57BL/6 background) developed significantly higher systolic blood pressure levels compared to C57BL/6 wild-type animals (136.0+/-3.0 mmHg vs. 112.2+/-2.6, P<0.01, n=16) as measured by the tail cuff method from week 6 up to week 12 post partum. The increase in blood pressure in p47phox-/- mice was associated with an impaired endothelium-dependent relaxation (P<0.005 vs. wild-type, n=11). At the age of 12 weeks p47phox-/- mice showed increased plasma renin activity as analyzed by radioimmunoassay (14.5+/-1.8 ng/mL/h vs. 9.6+/-1.7 ng/mL/h, P<0.05, n=10) and enhanced angiotensin converting enzyme (ACE) activity in the kidney and aorta as measured by Hip-His-Leu cleavage (7.6+/-0.8 vs. 4.8+/-0.9 nmol/L His-Leu/mg protein, P<0.05, n=5) compared to wild-type mice. No differences in oxygen radical formation was determined in kidney samples by lucigenin- and luminol-enhanced chemiluminescence or by electron spin resonance spectroscopy. Consistently, treatment with the radical scavenger tempol did not lower blood pressure in p47phox-/- mice, whereas ACE and angiotensin II type I receptor inhibition normalized blood pressure.

CONCLUSION

Deficiency of the NAD(P)H oxidase subunit p47phox leads to RAS activation, which subsequently contributes to blood pressure increase in a ROS-independent manner.

Authors+Show Affiliations

Department of Cardiology and Angiology, Medical School Hannover, Carl-Neuberg-Str. 1, D-30625 Hannover, Germany. Grote.Karsten@MH-Hannover.DENo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

16843452

Citation

Grote, Karsten, et al. "Critical Role for P47phox in Renin-angiotensin System Activation and Blood Pressure Regulation." Cardiovascular Research, vol. 71, no. 3, 2006, pp. 596-605.
Grote K, Ortmann M, Salguero G, et al. Critical role for p47phox in renin-angiotensin system activation and blood pressure regulation. Cardiovasc Res. 2006;71(3):596-605.
Grote, K., Ortmann, M., Salguero, G., Doerries, C., Landmesser, U., Luchtefeld, M., Brandes, R. P., Gwinner, W., Tschernig, T., Brabant, E. G., Klos, A., Schaefer, A., Drexler, H., & Schieffer, B. (2006). Critical role for p47phox in renin-angiotensin system activation and blood pressure regulation. Cardiovascular Research, 71(3), 596-605.
Grote K, et al. Critical Role for P47phox in Renin-angiotensin System Activation and Blood Pressure Regulation. Cardiovasc Res. 2006 Aug 1;71(3):596-605. PubMed PMID: 16843452.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Critical role for p47phox in renin-angiotensin system activation and blood pressure regulation. AU - Grote,Karsten, AU - Ortmann,Magdalene, AU - Salguero,Gustavo, AU - Doerries,Carola, AU - Landmesser,Ulf, AU - Luchtefeld,Maren, AU - Brandes,Ralf P, AU - Gwinner,Wilfried, AU - Tschernig,Thomas, AU - Brabant,Ernst-Georg, AU - Klos,Andreas, AU - Schaefer,Arnd, AU - Drexler,Helmut, AU - Schieffer,Bernhard, Y1 - 2006/05/26/ PY - 2005/11/30/received PY - 2006/05/04/revised PY - 2006/05/23/accepted PY - 2006/7/18/pubmed PY - 2006/10/7/medline PY - 2006/7/18/entrez SP - 596 EP - 605 JF - Cardiovascular research JO - Cardiovasc Res VL - 71 IS - 3 N2 - OBJECTIVE: Renin-angiotensin system (RAS) activation leads to increased production of NAD(P)H oxidase-derived reactive oxygen species (ROS), and both have been implicated in the initiation and progression of arterial hypertension, atherosclerosis, and cardiac hypertrophy. The cytosolic subunit p47phox is critically involved in agonist-induced NAD(P)H oxidase activation. Here, we investigated the role of p47phox in blood pressure control, endothelium-dependent relaxation, cardiac hypertrophy, RAS activation, and renal oxidative stress under resting conditions. METHODS AND RESULTS: Mice deficient in p47phox (on C57BL/6 background) developed significantly higher systolic blood pressure levels compared to C57BL/6 wild-type animals (136.0+/-3.0 mmHg vs. 112.2+/-2.6, P<0.01, n=16) as measured by the tail cuff method from week 6 up to week 12 post partum. The increase in blood pressure in p47phox-/- mice was associated with an impaired endothelium-dependent relaxation (P<0.005 vs. wild-type, n=11). At the age of 12 weeks p47phox-/- mice showed increased plasma renin activity as analyzed by radioimmunoassay (14.5+/-1.8 ng/mL/h vs. 9.6+/-1.7 ng/mL/h, P<0.05, n=10) and enhanced angiotensin converting enzyme (ACE) activity in the kidney and aorta as measured by Hip-His-Leu cleavage (7.6+/-0.8 vs. 4.8+/-0.9 nmol/L His-Leu/mg protein, P<0.05, n=5) compared to wild-type mice. No differences in oxygen radical formation was determined in kidney samples by lucigenin- and luminol-enhanced chemiluminescence or by electron spin resonance spectroscopy. Consistently, treatment with the radical scavenger tempol did not lower blood pressure in p47phox-/- mice, whereas ACE and angiotensin II type I receptor inhibition normalized blood pressure. CONCLUSION: Deficiency of the NAD(P)H oxidase subunit p47phox leads to RAS activation, which subsequently contributes to blood pressure increase in a ROS-independent manner. SN - 0008-6363 UR - https://www.unboundmedicine.com/medline/citation/16843452/Critical_role_for_p47phox_in_renin_angiotensin_system_activation_and_blood_pressure_regulation_ L2 - https://academic.oup.com/cardiovascres/article-lookup/doi/10.1016/j.cardiores.2006.05.020 DB - PRIME DP - Unbound Medicine ER -