Abstract
Introduction. Angiotensin II (AngII) activates p38 mitogen-activated protein kinase (MAPK) and elevates arginase activity in endothelial cells. Upregulation of arginase activity has been implicated in endothelial dysfunction by reducing nitric oxide (NO) bioavailability. However, signaling pathways activated by AngII in the penis are largely unknown.Aim. We hypothesized that activation of p38 MAPK increases arginase activity and thus impairs penile vascular function in AngII-treated mice.Methods. Male C57BL/6 mice were implanted with osmotic minipumps containing saline or AngII (42 μg/kg/h) for 14 days and cotreated with p38 MAPK inhibitor, SB 203580 (5 μg/kg/day), beginning 2 days before minipump implantation. Systolic blood pressure (SBP) was measured. Corpus cavernosum (CC) tissue was used for vascular functional studies and protein expression levels of p38 MAPK, arginase and constitutive NO synthase (NOS), and arginase activity.Main Outcome Measures. Arginase expression and activity; expression of phospho-p38 MAPK, endothelial NOS (eNOS) and neuronal NOS proteins; endothelium-dependent and nitrergic nerve-mediated relaxations were determined in CC from control and AngII-infused mice.Results. AngII increased SBP (22%) and increased CC arginase activity and expression (~twofold), and phosphorylated P38 MAPK levels (30%) over control. Treatment with SB 203580 prevented these effects. Endothelium-dependent NO-mediated relaxation to acetylcholine was significantly reduced by AngII and this effect was prevented by SB 203580 (P < 0.01). AngII (2 weeks) did not alter nitrergic function. However, SB 203580 significantly increased nitrergic relaxation in both control and AngII tissue at lower frequencies. Maximum contractile responses for phenylephrine and electrical field stimulation were increased by AngII (56% and 171%, respectively) and attenuated by SB 203580 treatment. AngII treatment also decreased eNOS phosphorylation at Ser-1177 compared to control. Treatment with SB 203580 prevented all these changes.Conclusion. p38 MAPK inhibition corrects penile arginase activity and protects against erectile dysfunction caused by AngII.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 3857-3867 |
| Number of pages | 11 |
| Journal | Journal of Sexual Medicine |
| Volume | 7 |
| Issue number | 12 |
| DOIs | |
| State | Published - Dec 2010 |
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Keywords
- Angiotensin II
- Arginase Activity
- Erectile Dysfunction
- Nitric Oxide
- P38 MAPK
ASJC Scopus subject areas
- Reproductive Medicine
- Obstetrics and Gynecology
- Urology
Cite this
p38 Mitogen-Activated Protein Kinase (MAPK) increases arginase activity and contributes to endothelial dysfunction in corpora cavernosa from angiotensin-II-treated mice. / Toque, Haroldo A.; Romero, Maritza J.; Tostes, Rita C.; Shatanawi, Alia; Chandra, Surabhi; Carneiro, Zidonia N.; Inscho, Edward W.; Webb, Robert Clinton; Caldwell, Ruth B.; Caldwell, Robert William.
In: Journal of Sexual Medicine, Vol. 7, No. 12, 12.2010, p. 3857-3867.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - p38 Mitogen-Activated Protein Kinase (MAPK) increases arginase activity and contributes to endothelial dysfunction in corpora cavernosa from angiotensin-II-treated mice
AU - Toque, Haroldo A.
AU - Romero, Maritza J.
AU - Tostes, Rita C.
AU - Shatanawi, Alia
AU - Chandra, Surabhi
AU - Carneiro, Zidonia N.
AU - Inscho, Edward W.
AU - Webb, Robert Clinton
AU - Caldwell, Ruth B.
AU - Caldwell, Robert William
PY - 2010/12
Y1 - 2010/12
N2 - Introduction. Angiotensin II (AngII) activates p38 mitogen-activated protein kinase (MAPK) and elevates arginase activity in endothelial cells. Upregulation of arginase activity has been implicated in endothelial dysfunction by reducing nitric oxide (NO) bioavailability. However, signaling pathways activated by AngII in the penis are largely unknown.Aim. We hypothesized that activation of p38 MAPK increases arginase activity and thus impairs penile vascular function in AngII-treated mice.Methods. Male C57BL/6 mice were implanted with osmotic minipumps containing saline or AngII (42 μg/kg/h) for 14 days and cotreated with p38 MAPK inhibitor, SB 203580 (5 μg/kg/day), beginning 2 days before minipump implantation. Systolic blood pressure (SBP) was measured. Corpus cavernosum (CC) tissue was used for vascular functional studies and protein expression levels of p38 MAPK, arginase and constitutive NO synthase (NOS), and arginase activity.Main Outcome Measures. Arginase expression and activity; expression of phospho-p38 MAPK, endothelial NOS (eNOS) and neuronal NOS proteins; endothelium-dependent and nitrergic nerve-mediated relaxations were determined in CC from control and AngII-infused mice.Results. AngII increased SBP (22%) and increased CC arginase activity and expression (~twofold), and phosphorylated P38 MAPK levels (30%) over control. Treatment with SB 203580 prevented these effects. Endothelium-dependent NO-mediated relaxation to acetylcholine was significantly reduced by AngII and this effect was prevented by SB 203580 (P < 0.01). AngII (2 weeks) did not alter nitrergic function. However, SB 203580 significantly increased nitrergic relaxation in both control and AngII tissue at lower frequencies. Maximum contractile responses for phenylephrine and electrical field stimulation were increased by AngII (56% and 171%, respectively) and attenuated by SB 203580 treatment. AngII treatment also decreased eNOS phosphorylation at Ser-1177 compared to control. Treatment with SB 203580 prevented all these changes.Conclusion. p38 MAPK inhibition corrects penile arginase activity and protects against erectile dysfunction caused by AngII.
AB - Introduction. Angiotensin II (AngII) activates p38 mitogen-activated protein kinase (MAPK) and elevates arginase activity in endothelial cells. Upregulation of arginase activity has been implicated in endothelial dysfunction by reducing nitric oxide (NO) bioavailability. However, signaling pathways activated by AngII in the penis are largely unknown.Aim. We hypothesized that activation of p38 MAPK increases arginase activity and thus impairs penile vascular function in AngII-treated mice.Methods. Male C57BL/6 mice were implanted with osmotic minipumps containing saline or AngII (42 μg/kg/h) for 14 days and cotreated with p38 MAPK inhibitor, SB 203580 (5 μg/kg/day), beginning 2 days before minipump implantation. Systolic blood pressure (SBP) was measured. Corpus cavernosum (CC) tissue was used for vascular functional studies and protein expression levels of p38 MAPK, arginase and constitutive NO synthase (NOS), and arginase activity.Main Outcome Measures. Arginase expression and activity; expression of phospho-p38 MAPK, endothelial NOS (eNOS) and neuronal NOS proteins; endothelium-dependent and nitrergic nerve-mediated relaxations were determined in CC from control and AngII-infused mice.Results. AngII increased SBP (22%) and increased CC arginase activity and expression (~twofold), and phosphorylated P38 MAPK levels (30%) over control. Treatment with SB 203580 prevented these effects. Endothelium-dependent NO-mediated relaxation to acetylcholine was significantly reduced by AngII and this effect was prevented by SB 203580 (P < 0.01). AngII (2 weeks) did not alter nitrergic function. However, SB 203580 significantly increased nitrergic relaxation in both control and AngII tissue at lower frequencies. Maximum contractile responses for phenylephrine and electrical field stimulation were increased by AngII (56% and 171%, respectively) and attenuated by SB 203580 treatment. AngII treatment also decreased eNOS phosphorylation at Ser-1177 compared to control. Treatment with SB 203580 prevented all these changes.Conclusion. p38 MAPK inhibition corrects penile arginase activity and protects against erectile dysfunction caused by AngII.
KW - Angiotensin II
KW - Arginase Activity
KW - Erectile Dysfunction
KW - Nitric Oxide
KW - P38 MAPK
UR - http://www.scopus.com/inward/record.url?scp=78649844792&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=78649844792&partnerID=8YFLogxK
U2 - 10.1111/j.1743-6109.2010.01996.x
DO - 10.1111/j.1743-6109.2010.01996.x
M3 - Article
C2 - 20807329
AN - SCOPUS:78649844792
VL - 7
SP - 3857
EP - 3867
JO - Journal of Sexual Medicine
JF - Journal of Sexual Medicine
SN - 1743-6095
IS - 12
ER -