Targeting Gα i2 in neutrophils protects from myocardial ischemia reperfusion injury.
David KöhlerVeronika LeissLukas BeichertSimon KillingerDaniela GrotheRagini KushwahaAgnes SchröterAnna RoslanClaudia EggsteinJule FockenTiago GranjaVasudharani DevanathanBirgit SchittekRobert LukowskiBettina WeigelinPeter RosenbergerBernd NürnbergSandra Beer-HammerPublished in: Basic research in cardiology (2024)
Neutrophils are not only involved in immune defense against infection but also contribute to the exacerbation of tissue damage after ischemia and reperfusion. We have previously shown that genetic ablation of regulatory Gα i proteins in mice has both protective and deleterious effects on myocardial ischemia reperfusion injury (mIRI), depending on which isoform is deleted. To deepen and analyze these findings in more detail the contribution of Gα i2 proteins in resident cardiac vs circulating blood cells for mIRI was first studied in bone marrow chimeras. In fact, the absence of Gα i2 in all blood cells reduced the extent of mIRI (22,9% infarct size of area at risk (AAR) Gnai2 -/- → wt vs 44.0% wt → wt; p < 0.001) whereas the absence of Gα i2 in non-hematopoietic cells increased the infarct damage (66.5% wt → Gnai2 -/- vs 44.0% wt → wt; p < 0.001). Previously we have reported the impact of platelet Gα i2 for mIRI. Here, we show that infarct size was substantially reduced when Gα i2 signaling was either genetically ablated in neutrophils/macrophages using LysM-driven Cre recombinase (AAR: 17.9% Gnai2 fl/fl LysM-Cre +/tg vs 42.0% Gnai2 fl/fl ; p < 0.01) or selectively blocked with specific antibodies directed against Gα i2 (AAR: 19.0% (anti-Gα i2 ) vs 49.0% (IgG); p < 0.001). In addition, the number of platelet-neutrophil complexes (PNCs) in the infarcted area were reduced in both, genetically modified (PNCs: 18 (Gnai2 fl/fl ; LysM-Cre +/tg ) vs 31 (Gnai2 fl/fl ); p < 0.001) and in anti-Gα i2 antibody-treated (PNCs: 9 (anti-Gα i2 ) vs 33 (IgG); p < 0.001) mice. Of note, significant infarct-limiting effects were achieved with a single anti-Gα i2 antibody challenge immediately prior to vessel reperfusion without affecting bleeding time, heart rate or cellular distribution of neutrophils. Finally, anti-Gα i2 antibody treatment also inhibited transendothelial migration of human neutrophils (25,885 (IgG) vs 13,225 (anti-Gα i2 ) neutrophils; p < 0.001), collectively suggesting that a therapeutic concept of functional Gα i2 inhibition during thrombolysis and reperfusion in patients with myocardial infarction should be further considered.
Keyphrases
- acute myocardial infarction
- induced apoptosis
- ischemia reperfusion injury
- heart rate
- bone marrow
- oxidative stress
- left ventricular
- cell cycle arrest
- acute ischemic stroke
- endothelial cells
- heart rate variability
- chronic obstructive pulmonary disease
- transcription factor
- mesenchymal stem cells
- endoplasmic reticulum stress
- signaling pathway
- type diabetes
- quality improvement
- dna methylation
- insulin resistance
- atrial fibrillation
- metabolic syndrome
- adipose tissue
- acute coronary syndrome
- copy number
- smoking cessation
- cancer therapy
- pluripotent stem cells
- respiratory failure