Dimethylarginine dimethylaminohydrolase1 is an organ-specific mediator of end organ damage in a murine model of hypertension.
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Dimethylarginine dimethylaminohydrolase1 is an organ-specific mediator of end organ damage in a murine model of hypertension. / Sydow, Karsten; Schmitz, Christine; von Leitner, Eike-Christin; von Leitner, Robin; Klinke, Anna; Atzler, Dorothee; Krebs, Christian; Wieboldt, Hartwig; Ehmke, Heimo; Schwedhelm, Edzard; Meinertz, Thomas; Blankenberg, Stefan; Böger, Rainer H; Magnus, Tim; Baldus, Stephan; Wenzel, Ulrich.
In: PLOS ONE, Vol. 7, No. 10, 10, 2012, p. 48150.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Dimethylarginine dimethylaminohydrolase1 is an organ-specific mediator of end organ damage in a murine model of hypertension.
AU - Sydow, Karsten
AU - Schmitz, Christine
AU - von Leitner, Eike-Christin
AU - von Leitner, Robin
AU - Klinke, Anna
AU - Atzler, Dorothee
AU - Krebs, Christian
AU - Wieboldt, Hartwig
AU - Ehmke, Heimo
AU - Schwedhelm, Edzard
AU - Meinertz, Thomas
AU - Blankenberg, Stefan
AU - Böger, Rainer H
AU - Magnus, Tim
AU - Baldus, Stephan
AU - Wenzel, Ulrich
PY - 2012
Y1 - 2012
N2 - BACKGROUND: The endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA) is an independent predictor of cardiovascular and overall mortality. Moreover, elevated ADMA plasma concentrations are associated with the extent of hypertension. However, data from small-sized clinical trials and experimental approaches using murine transgenic models have revealed conflicting results regarding the impact of ADMA and its metabolizing enzyme dimethylarginine dimethylaminohydrolase (DDAH) in the pathogenesis of hypertension.METHODOLOGY/PRINCIPAL FINDINGS: Therefore, we investigated the role of ADMA and DDAH1 in hypertension-induced end organ damage using the uninephrectomized, deoxycorticosterone actetate salt, and angiotensin II-induced hypertension model in human DDAH1 (hDDAH1) overexpressing and wild-type (WT) mice. ADMA plasma concentrations differed significantly between hDDAH1 and WT mice at baseline, but did not significantly change during the induction of hypertension. hDDAH1 overexpression did not protect against hypertension-induced cardiac fibrosis and hypertrophy. In addition, the hypertension-induced impairment of the endothelium-dependent vasorelaxation of aortic segments ex vivo was not significantly attenuated by hDDAH1 overexpression. However, hDDAH1 mice displayed an attenuated hypertensive inflammatory response in renal tissue, resulting in less hypertensive renal injury.CONCLUSION/SIGNIFICANCE: Our data reveal that hDDAH1 organ-specifically modulates the inflammatory response in this murine model of hypertension. The lack of protection in cardiac and aortic tissues may be due to DDAH1 tissue selectivity and/or the extent of hypertension by the used combined model. However, our study underlines the potency of hDDAH1 overexpression in modulating inflammatory processes as a crucial step in the pathogenesis of hypertension, which needs further experimental and clinical investigation.
AB - BACKGROUND: The endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA) is an independent predictor of cardiovascular and overall mortality. Moreover, elevated ADMA plasma concentrations are associated with the extent of hypertension. However, data from small-sized clinical trials and experimental approaches using murine transgenic models have revealed conflicting results regarding the impact of ADMA and its metabolizing enzyme dimethylarginine dimethylaminohydrolase (DDAH) in the pathogenesis of hypertension.METHODOLOGY/PRINCIPAL FINDINGS: Therefore, we investigated the role of ADMA and DDAH1 in hypertension-induced end organ damage using the uninephrectomized, deoxycorticosterone actetate salt, and angiotensin II-induced hypertension model in human DDAH1 (hDDAH1) overexpressing and wild-type (WT) mice. ADMA plasma concentrations differed significantly between hDDAH1 and WT mice at baseline, but did not significantly change during the induction of hypertension. hDDAH1 overexpression did not protect against hypertension-induced cardiac fibrosis and hypertrophy. In addition, the hypertension-induced impairment of the endothelium-dependent vasorelaxation of aortic segments ex vivo was not significantly attenuated by hDDAH1 overexpression. However, hDDAH1 mice displayed an attenuated hypertensive inflammatory response in renal tissue, resulting in less hypertensive renal injury.CONCLUSION/SIGNIFICANCE: Our data reveal that hDDAH1 organ-specifically modulates the inflammatory response in this murine model of hypertension. The lack of protection in cardiac and aortic tissues may be due to DDAH1 tissue selectivity and/or the extent of hypertension by the used combined model. However, our study underlines the potency of hDDAH1 overexpression in modulating inflammatory processes as a crucial step in the pathogenesis of hypertension, which needs further experimental and clinical investigation.
KW - Animals
KW - Humans
KW - Male
KW - Mice
KW - Mice, Inbred C57BL
KW - Mice, Transgenic
KW - Blood Pressure/physiology
KW - Arginine/analogs & derivatives/blood
KW - Amidohydrolases/genetics/metabolism
KW - Heart/physiology
KW - Hypertension/blood/enzymology/genetics
KW - Kidney/metabolism/physiology
KW - Animals
KW - Humans
KW - Male
KW - Mice
KW - Mice, Inbred C57BL
KW - Mice, Transgenic
KW - Blood Pressure/physiology
KW - Arginine/analogs & derivatives/blood
KW - Amidohydrolases/genetics/metabolism
KW - Heart/physiology
KW - Hypertension/blood/enzymology/genetics
KW - Kidney/metabolism/physiology
U2 - 10.1371/journal.pone.0048150
DO - 10.1371/journal.pone.0048150
M3 - SCORING: Journal article
C2 - 23110194
VL - 7
SP - 48150
JO - PLOS ONE
JF - PLOS ONE
SN - 1932-6203
IS - 10
M1 - 10
ER -
