Heme stimulates platelet mitochondrial oxidant production to induce targeted granule secretion

Annarapu, Gowtham K.; Nolfi‐Donegan, Deirdre; Reynolds, Michael; Wang, Yinna; Kohut, Lauryn; Zuckerbraun, Brian S.; Shiva, Sruti

doi:10.1016/j.redox.2021.102205

Cited by 8 publications

(17 citation statements)

References 86 publications

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“…Activated PLCγ2 usually catalyzes phosphatidylinositol-4,5-bisphosphate (PIP 2 ) hydrolysis to inositol trisphosphate (IP 3 ) and diacylglycerol (DAG), leading to calcium mobilization and protein kinase C (PKC) activation [ 51 ]. A heme-induced increase in IP3 and DAG levels has not yet been described; however, elevated intracellular calcium levels and mobilization in platelets as well as PKC activation in neutrophils has already been monitored (in the presence of up to 20 µM heme) [ 46 , 57 , 58 ]. In general, calcium mobilization enables contractile activity through myosin, which leads to the characteristic shape change of activated platelets [ 50 ].…”

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

“…Apart from PLC activation (see above), PI3K can catalyze Akt phosphorylation, explaining its activation in platelets upon incubation with heme (2.5 µM) [ 57 ]. Heme-triggered platelet activation along with Akt phosphorylation was demonstrated to be dependent on TLR4 [ 57 ]. Although the TLR4 signaling pathway is highly pronounced in the HemeThrombKG network, it did not emerge during crosstalk analysis, since it is not yet recognized for its contribution to procoagulant processes in the databases.…”

Section: Resultsmentioning

confidence: 99%

“…Akt phosphorylation can further lead to eNOS activation in platelets, a hemoprotein, whose production has been reported to be influenced by heme [ 61 , 62 ]. Many of the subsequent effector proteins of this pathway have not yet been described in relation to heme signaling, but ERK has been found to contribute to heme signaling in other cell types (e.g., neutrophils) ( Table S1 ) [ 43 , 57 , 63 ]. Furthermore, an interrelation of heme with the messenger molecules cyclic guanosine monophosphate (cGMP; in vivo), arachidonic acid, and thromboxane A2 (in vitro) in platelets has already been reported [ 46 , 64 , 65 , 66 ], suggesting the induction and progression of the respective pathways in the presence of heme.…”

Section: Resultsmentioning

confidence: 99%

“…Beyond the effects on the coagulation cascade, heme has been associated with cellular events, including platelet adhesion, activation, and aggregation [ 46 , 53 , 55 , 57 , 67 ]. However, the underlying intracellular signaling pathways and, in particular, the interrelations of the already described effector proteins, are largely unexplored.…”

Section: Discussionmentioning

confidence: 99%

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Exploring the Complex Network of Heme-Triggered Effects on the Blood Coagulation System

Mubeen

Domingo‐Fernándéz

Ser

et al. 2022

JCM

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Excess labile heme, occurring under hemolytic conditions, displays a versatile modulator in the blood coagulation system. As such, heme provokes prothrombotic states, either by binding to plasma proteins or through interaction with participating cell types. However, despite several independent reports on these effects, apparently contradictory observations and significant knowledge gaps characterize this relationship, which hampers a complete understanding of heme-driven coagulopathies and the development of suitable and specific treatment options. Thus, the computational exploration of the complex network of heme-triggered effects in the blood coagulation system is presented herein. Combining hemostasis- and heme-specific terminology, the knowledge available thus far was curated and modeled in a mechanistic interactome. Further, these data were incorporated in the earlier established heme knowledge graph, “HemeKG”, to better comprehend the knowledge surrounding heme biology. Finally, a pathway enrichment analysis of these data provided deep insights into so far unknown links and novel experimental targets within the blood coagulation cascade and platelet activation pathways for further investigation of the prothrombotic nature of heme. In summary, this study allows, for the first time, a detailed network analysis of the effects of heme in the blood coagulation system.

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