Platelet Gᵢ protein Gαᵢ₂ is an essential mediator of thrombo-inflammatory organ damage in mice

Platelets are crucial for hemostasis and thrombosis and exacerbate tissue injury following ischemia and reperfusion. Important regulators of platelet function are G proteins controlled by seven transmembrane receptors. The G ᵢ protein Gα ᵢ₂ mediates platelet activation in vitro, but its in vivo role in hemostasis, arterial thrombosis, and postischemic infarct progression remains to be determined. Here we show that mice lacking Gα ᵢ₂ exhibit prolonged tail-bleeding times and markedly impaired thrombus formation and stability in different models of arterial thrombosis. We thus generated mice selectively lacking Gα ᵢ₂ in megakaryocytes and platelets ( Gnai2 ᶠˡ/ᶠˡ/PF4-Cre mice) and found bleeding defects comparable to those in global Gα ᵢ₂-deficient mice. To examine the impact of platelet Gα ᵢ₂ in postischemic thrombo-inflammatory infarct progression, Gnai2 ᶠˡ/ᶠˡ/PF4 -Cre mice were subjected to experimental models of cerebral and myocardial ischemia/reperfusion injury. In the model of transient middle cerebral artery occlusion stroke Gnai2 ᶠˡ/ᶠˡ/PF4 -Cre mice developed significantly smaller brain infarcts and fewer neurological deficits than littermate controls. Following myocardial ischemia, Gnai2 ᶠˡ/ᶠˡ/PF4 -Cre mice showed dramatically reduced reperfusion injury which correlated with diminished formation of the ADP-dependent platelet neutrophil complex. In conclusion, our data provide definitive evidence that platelet Gα ᵢ₂ not only controls hemostatic and thrombotic responses but also is critical for the development of ischemia/reperfusion injury in vivo. Significance Platelet activation is crucial for hemostasis and thrombosis but also contributes to inflammation and progression of tissue damage following ischemia/reperfusion injury. Here we demonstrate that platelet activation through the G ᵢ protein Gα ᵢ₂ not only controls hemostatic responses but also thrombo-inflammatory tissue damage following cerebral and cardiac ischemia. Our report on a dual role of G ᵢ proteins in platelet function opens new options for pharmaco-therapeutic strategies fighting ischemic diseases such as heart attack and stroke.