What question did this study set out to answer?

To determine whether angiotensin-converting enzyme (ACE) possesses intrinsic signal transduction capabilities and whether ACE inhibitors modulate this intracellular signaling via ACE phosphorylation.

November 18, 2003Circulation ResearchOpen Access

Angiotensin-Converting Enzyme Is Involved in Outside-In Signaling in Endothelial Cells

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Population

Cultured endothelial cells, S1270A ACE mutant cells, ACE-deficient cells, and in vivo mouse lung models

Comparison

ACE inhibitors, bradykinin, and JNK inhibitor… vs Untreated/control cells and mice

Design

Preclinical

Authors

KKKarin KohlstedtUniversity of Applied Sciences Potsdam RBRalf P. BrandesVascular / Pulmonary Vascular WMWerner Müller‐EsterlGoethe University Frankfurt

Discussion

Member takes

Implication

May contribute to ACE inhibitor vascular benefits; leaves open confirmation in human models.

Key Points

To determine whether angiotensin-converting enzyme (ACE) possesses intrinsic signal transduction capabilities and whether ACE inhibitors modulate this intracellular signaling via ACE phosphorylation.
Stimulated cultured endothelial cells, S1270A ACE mutant-expressing cells, and ACE-deficient cells with ACE inhibitors (ramiprilat, perindoprilat) or substrates (bradykinin, angiotensin I).
Assessed protein-protein interactions, CK2 activity, Ser1270 phosphorylation, JNK activation, and nuclear accumulation of phosphorylated c-Jun.
Evaluated chronic ramiprilat-induced ACE expression in primary human endothelial cells and in mouse lung tissue in the presence or absence of the JNK inhibitor SP600125.
Ramiprilat, perindoprilat, and bradykinin stimulated ACE-associated CK2 activity and induced phosphorylation of ACE at Ser1270 in cultured endothelial cells.
ACE inhibitor treatment promoted coprecipitation of MKK7 and JNK with ACE, activated ACE-associated JNK, and triggered nuclear translocation of phosphorylated c-Jun; these effects were absent in S1270A mutants and ACE-deficient cells.
Prolonged ramiprilat administration upregulated ACE expression in human endothelial cells and mouse lung tissue, which was fully blocked by pharmacological inhibition of JNK.

Structured PICO

Population

Cultured endothelial cells (including primary cultures of human endothelial cells), S1270A ACE mutant cells, ACE-deficient cells, and in vivo mouse lung models

Intervention

ACE inhibitors (ramiprilat and perindoprilat), bradykinin, and JNK inhibitor SP600125

Comparator

Untreated/control cells and mice

Outcome

Phosphorylation of ACE Ser1270 and activation of signal transduction pathways (CK2, JNK, c-Jun)surrogate

ACE acts as a signal transduction molecule in endothelial cells, and ACE inhibitor-induced outside-in signaling via JNK contributes to increased ACE expression, potentially explaining some beneficial cardiovascular effects of ACE inhibitors.

Cite This Study

Kohlstedt et al. (2003) studied this question.

synapsesocial.com/papers/6a70fb0f75498292b70a7790 https://doi.org/10.1161/01.res.0000107195.13573.e4

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Angiotensin-Converting Enzyme Is Involved in Outside-In Signaling in Endothelial Cells

Discussion

Member takes

Implication

Key Points

Structured PICO

Cite This Study

Angiotensin-Converting Enzyme Is Involved in Outside-In Signaling in Endothelial Cells

Discussion

Member takes

Implication

Key Points

Structured PICO

Cite This Study

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