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Vascular neuronal NO synthase is selectively upregulated by platelet-derived growth factor: involvement of the MEK/ERK pathway.
Arterioscler Thromb Vasc Biol 2005; 25(12):2502-8AT

Abstract

OBJECTIVE

We demonstrated recently that neuronal NO synthase (NOS) is expressed in arteriosclerotic lesions and exerts important vasculoprotective effects in vivo. In this study, we examined the molecular mechanism(s) for vascular neuronal NOS (nNOS) expression.

METHODS AND RESULTS

In cultured rat aortic smooth muscle cells, treatment with platelet-derived growth factor (PDGF) selectively upregulated nNOS expression but not inducible NOS (iNOS) or endothelial NOS (eNOS) expression. Treatment with PDGF also significantly caused activation of mitogen-activated protein kinase (MAPK) family, including extracellular signal-regulated kinase (ERK), p38MAPK, and c-Jun N-terminal kinase (JNK). ERK kinase (MAPK kinase [MEK]) inhibitors inhibited PDGF-induced nNOS expression, whereas a p38MAPK inhibitor or JNK inhibitor was without effects. Importantly, gene transfer of MEK per se elicited nNOS induction, and gene transfer of dominant-negative MEK abolished PDGF-induced nNOS expression. In isolated aortas of wild-type, eNOS(-/-), and iNOS(-/-) mice, but not in those of nNOS(-/-) mice, treatment with PDGF significantly enhanced nNOS expression and nitrite plus nitrate production, both of which were again attenuated by a MEK inhibitor.

CONCLUSIONS

These results provide the first evidence that vascular nNOS expression is upregulated selectively in response to PDGF through the MEK/ERK pathway. Upregulated nNOS may play an important compensatory role under arteriosclerotic/inflammatory conditions associated with eNOS dysfunction to maintain vascular homeostasis.

Authors+Show Affiliations

Second Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan.No 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

16224055

Citation

Nakata, Sei, et al. "Vascular Neuronal NO Synthase Is Selectively Upregulated By Platelet-derived Growth Factor: Involvement of the MEK/ERK Pathway." Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 25, no. 12, 2005, pp. 2502-8.
Nakata S, Tsutsui M, Shimokawa H, et al. Vascular neuronal NO synthase is selectively upregulated by platelet-derived growth factor: involvement of the MEK/ERK pathway. Arterioscler Thromb Vasc Biol. 2005;25(12):2502-8.
Nakata, S., Tsutsui, M., Shimokawa, H., Tamura, M., Tasaki, H., Morishita, T., ... Yanagihara, N. (2005). Vascular neuronal NO synthase is selectively upregulated by platelet-derived growth factor: involvement of the MEK/ERK pathway. Arteriosclerosis, Thrombosis, and Vascular Biology, 25(12), pp. 2502-8.
Nakata S, et al. Vascular Neuronal NO Synthase Is Selectively Upregulated By Platelet-derived Growth Factor: Involvement of the MEK/ERK Pathway. Arterioscler Thromb Vasc Biol. 2005;25(12):2502-8. PubMed PMID: 16224055.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Vascular neuronal NO synthase is selectively upregulated by platelet-derived growth factor: involvement of the MEK/ERK pathway. AU - Nakata,Sei, AU - Tsutsui,Masato, AU - Shimokawa,Hiroaki, AU - Tamura,Masahito, AU - Tasaki,Hiromi, AU - Morishita,Tsuyoshi, AU - Suda,Osamu, AU - Ueno,Susumu, AU - Toyohira,Yumiko, AU - Nakashima,Yasuhide, AU - Yanagihara,Nobuyuki, Y1 - 2005/10/13/ PY - 2005/10/15/pubmed PY - 2006/1/21/medline PY - 2005/10/15/entrez SP - 2502 EP - 8 JF - Arteriosclerosis, thrombosis, and vascular biology JO - Arterioscler. Thromb. Vasc. Biol. VL - 25 IS - 12 N2 - OBJECTIVE: We demonstrated recently that neuronal NO synthase (NOS) is expressed in arteriosclerotic lesions and exerts important vasculoprotective effects in vivo. In this study, we examined the molecular mechanism(s) for vascular neuronal NOS (nNOS) expression. METHODS AND RESULTS: In cultured rat aortic smooth muscle cells, treatment with platelet-derived growth factor (PDGF) selectively upregulated nNOS expression but not inducible NOS (iNOS) or endothelial NOS (eNOS) expression. Treatment with PDGF also significantly caused activation of mitogen-activated protein kinase (MAPK) family, including extracellular signal-regulated kinase (ERK), p38MAPK, and c-Jun N-terminal kinase (JNK). ERK kinase (MAPK kinase [MEK]) inhibitors inhibited PDGF-induced nNOS expression, whereas a p38MAPK inhibitor or JNK inhibitor was without effects. Importantly, gene transfer of MEK per se elicited nNOS induction, and gene transfer of dominant-negative MEK abolished PDGF-induced nNOS expression. In isolated aortas of wild-type, eNOS(-/-), and iNOS(-/-) mice, but not in those of nNOS(-/-) mice, treatment with PDGF significantly enhanced nNOS expression and nitrite plus nitrate production, both of which were again attenuated by a MEK inhibitor. CONCLUSIONS: These results provide the first evidence that vascular nNOS expression is upregulated selectively in response to PDGF through the MEK/ERK pathway. Upregulated nNOS may play an important compensatory role under arteriosclerotic/inflammatory conditions associated with eNOS dysfunction to maintain vascular homeostasis. SN - 1524-4636 UR - https://www.unboundmedicine.com/medline/citation/16224055/Vascular_neuronal_NO_synthase_is_selectively_upregulated_by_platelet_derived_growth_factor:_involvement_of_the_MEK/ERK_pathway_ L2 - http://www.ahajournals.org/doi/full/10.1161/01.ATV.0000190663.88143.97?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -