Antiplatelet effect of spironolactone via modulation of cPLA₂-mediated thromboxane A₂ generation in murine platelets.
- 1Laboratory of Veterinary Pathology and Platelet Signaling, College of Veterinary Medicine, Chungbuk National University, Cheongju 28644, Korea.
- 2Molecular Cardiology Research Institute, Tufts University School of Medicine, Boston, MA 02111, USA.
- 3Cancer Research Center, Chungbuk National University, Cheongju 28644, Korea. [email protected].
Abstract
Importance
Spironolactone, a steroidal aldosterone antagonist, is widely used as a diuretic and antihypertensive agent. Steroids have been known to promote thrombosis by directly increasing platelet count and activation and indirectly by increasing oxidative stress and suppressing nitric oxide synthesis. However, the effects of spironolactone on platelet activation remain unclear.Objective
To investigate the effects of spironolactone on platelet function and underlying signaling mechanisms.Methods
Platelet aggregation, dense granule secretion, thromboxane A₂ (TxA₂) generation, and protein phosphorylation were evaluated in platelets treated with spironolactone.Results
Spironolactone significantly inhibited the secondary wave of platelet aggregation and dense granule secretion induced by 2-methylthioadenosine diphosphate (2-MeSADP). It is known that 2-MeSADP-induced secretion and the resultant secondary wave of aggregation depend on TxA₂-mediated positive feedback, suggesting a role for spironolactone in regulating TxA₂ generation in platelets. Additionally, spironolactone did not affect 2-MeSADP-induced platelet aggregation in aspirin-treated platelets in which TxA₂ generation was blocked. Furthermore, platelet aggregation and secretion induced by low concentrations of thrombin, which are also affected by TxA₂-mediated positive feedback, were partially inhibited by spironolactone. Notably, spironolactone significantly suppressed TxA₂ generation induced by both 2-MeSADP and thrombin. Finally, spironolactone markedly inhibited the 2-MeSADP- and thrombin-induced phosphorylation of cytosolic phospholipase A₂ (cPLA₂), extracellular signal-regulated kinase, and protein kinase B in non-aspirin-treated platelets, whereas only cPLA₂ phosphorylation was significantly inhibited in aspirin-treated platelets.Conclusions and relevance
Spironolactone inhibits platelet activation by suppressing TxA₂ generation, primarily by modulating cPLA₂ phosphorylation, providing mechanistic insight into its effects on platelet signaling in vitro.
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BibTeX
@article{kim2026antiplatelet,
title = {{Antiplatelet effect of spironolactone via modulation of cPLA₂-mediated thromboxane A₂ generation in murine platelets.}},
author = {Sanggu Kim and Preeti Kumari Chaudhary and Seongmo Yang and Soochong Kim},
journal = {Journal of veterinary science},
year = {2026},
month = sep,
doi = {10.4142/jvs.26033},
url = {https://europepmc.org/article/MED/42847795},
note = {CC BY},
}
RIS
TY - JOUR
TI - Antiplatelet effect of spironolactone via modulation of cPLA₂-mediated thromboxane A₂ generation in murine platelets.
AU - Sanggu Kim
AU - Preeti Kumari Chaudhary
AU - Seongmo Yang
AU - Soochong Kim
PY - 2026
DA - 2026/09/01
JO - Journal of veterinary science
DO - 10.4142/jvs.26033
UR - https://europepmc.org/article/MED/42847795
AB - Importance Spironolactone, a steroidal aldosterone antagonist, is widely used as a diuretic and antihypertensive agent. Steroids have been known to promote thrombosis by directly increasing platelet count and activation and indirectly by increasing oxidative stress and suppressing nitric oxide synthesis. However, the effects of spironolactone on platelet activation remain unclear.Objective To investigate the effects of spironolactone on platelet function and underlying signaling mechanisms.Methods Platelet aggregation, dense granule secretion, thromboxane A₂ (TxA₂) generation, and protein phosphorylation were evaluated in platelets treated with spironolactone.Results Spironolactone significantly inhibited the secondary wave of platelet aggregation and dense granule secretion induced by 2-methylthioadenosine diphosphate (2-MeSADP). It is known that 2-MeSADP-induced secretion and the resultant secondary wave of aggregation depend on TxA₂-mediated positive feedback, suggesting a role for spironolactone in regulating TxA₂ generation in platelets. Additionally, spironolactone did not affect 2-MeSADP-induced platelet aggregation in aspirin-treated platelets in which TxA₂ generation was blocked. Furthermore, platelet aggregation and secretion induced by low concentrations of thrombin, which are also affected by TxA₂-mediated positive feedback, were partially inhibited by spironolactone. Notably, spironolactone significantly suppressed TxA₂ generation induced by both 2-MeSADP and thrombin. Finally, spironolactone markedly inhibited the 2-MeSADP- and thrombin-induced phosphorylation of cytosolic phospholipase A₂ (cPLA₂), extracellular signal-regulated kinase, and protein kinase B in non-aspirin-treated platelets, whereas only cPLA₂ phosphorylation was significantly inhibited in aspirin-treated platelets.Conclusions and relevance Spironolactone inhibits platelet activation by suppressing TxA₂ generation, primarily by modulating cPLA₂ phosphorylation, providing mechanistic insight into its effects on platelet signaling in vitro.
SN - 1229-845X
SN - 1976-555X
ER -