Elevated angiotensin II induces platelet apoptosis through promoting oxidative stress in an AT1R‐dependent manner during sepsis

Abstract

Thrombocytopenia is independently related with increased mortality in severe septic patients. Renin‐angiotensin system (RAS) is elevated in septic subjects; accumulating studies show that angiotensin II (Ang II) stimulate the intrinsic apoptosis pathway by promoting reactive oxygen species (ROS) production. However, the mechanisms underlying the relationship of platelet apoptosis and RAS system in sepsis have not been fully elucidated. The present study aimed to elucidate whether the RAS was involved in the pathogenesis of sepsis‐associated thrombocytopenia and explore the underlying mechanisms. We found that elevated plasma Ang II was associated with decreased platelet count in both patients with sepsis and experimental animals exposed to lipopolysaccharide (LPS). Besides, Ang II treatment induced platelet apoptosis in a concentration‐dependent manner in primary isolated platelets, which was blocked by angiotensin II type 1 receptor (AT1R) antagonist losartan, but not by angiotensin II type 2 receptor (AT2R) antagonist PD123319. Moreover, inhibiting AT1R by losartan attenuated LPS‐induced platelet apoptosis and alleviated sepsis‐associated thrombocytopenia. Furthermore, Ang II treatment induced oxidative stress level in a concentration‐dependent manner in primary isolated platelets, which was partially reversed by the AT1R antagonist losartan. The present study demonstrated that elevated Ang II directly stimulated platelet apoptosis through promoting oxidative stress in an AT1R‐dependent manner in sepsis‐associated thrombocytopenia. The results would helpful for understanding the role of RAS system in sepsis‐associated thrombocytopenia.

Angiotensin-(1–7) ameliorates sepsis-induced cardiomyopathy by alleviating inflammatory response and mitochondrial damage through the NF-κB and MAPK pathways

“…When sepsis occurs, the host Ang II/AT1R and the Ang-(1-7)/MasR axes become imbalanced, Ang II levels are elevated and it is associated with microvascular dysregulation and organ damage [29]. Additionally, Ang II can be regarded as the predictor of mortality in septic patients, and the earlier use of AT1R blockers (ARBs) could decrease short-term mortality in septic patients [30][31][32][33][34].…”

The 3-iodothyronamine (T1AM) and the 3-iodothyroacetic acid (TA1) indicate a novel connection with the histamine system for neuroprotection

“…These molecules achieve their effects by means of their chemical structure, acting as reducing agents, detoxifying ROS, or "indirectly" preventing ROS formation. This latter class includes compounds controlling the expression/activity of ROS-generating or ROSdetoxifying proteins [18,19]. In this respect, less is known about the antioxidant/prooxidant capacity of T1AM and TA1 and whether they can exert control on the expression/activity of the MAO and SSAO, enzymes included in the pharmacokinetics of T1AM and on the antioxidant deacetylase SIRT1.…”

Gasdermin D-dependent platelet pyroptosis exacerbates NET formation and inflammation in severe sepsis

“…Thrombocytopenia in severe sepsis is caused by altered platelet production, hemophagocytosis, antibodies, disseminated intravascular coagulation or platelet scavenging in the circulation due to platelet–leukocyte or platelet–pathogen interactions, vessel injury or desialylation 36 . A recent report suggested that elevated angiotensin II induced platelet apoptosis, leading to sepsis-associated thrombocytopenia 37 . In our study, GSDMD-dependent pyroptosis slightly reduced platelet counts, but was not a major contributor to thrombocytopenia in sepsis.…”