Tissue-specific adaptations to cytochrome c oxidase deficiency shape physiological outcomes.

It becomes increasingly clear that the tissue specificity of mitochondrial diseases might in part rely on their ability to compensate for mitochondrial defects, contributing to the heterogeneous nature of mitochondrial diseases. Here, we investigated tissue-specific responses to cytochrome c oxidase (CIV or COX) deficiency using a mouse model with heart and skeletal muscle-specific depletion of the COX assembly factor COX10. At three weeks of age, both tissues exhibit pronounced CIV depletion but respond differently to oxidative phosphorylation (OXPHOS) impairment.

Hematopoietic PI3Kδ deficiency aggravates murine atherosclerosis through impairment of Tregs.

Chronic activation of the adaptive immune system is a hallmark of atherosclerosis. As PI3Kδ is a key regulator of T and B cell differentiation and function, we hypothesized that alleviation of adaptive immunity by PI3Kδ inactivation may represent an attractive strategy counteracting atherogenesis. As expected, lack of hematopoietic PI3Kδ in atherosclerosis-prone Ldlr-/- mice resulted in lowered T and B cell numbers, CD4+ effector T cells, Th1 response, and immunoglobulin levels.

Inhibition of myeloperoxidase to treat left ventricular dysfunction in non-ischaemic cardiomyopathy.

Aims: Non-ischaemic cardiomyopathy (NICMP), an incurable disease terminating in systolic heart failure (heart failure with reduced ejection fraction [HFrEF]), causes immune activation, however anti-inflammatory treatment strategies so far have failed to alter the course of this disease. Myeloperoxidase (MPO), the principal enzyme in neutrophils, has cytotoxic, pro-fibrotic and nitric oxide oxidizing effects. Whether MPO inhibition ameliorates the phenotype in NICMP remains elusive.

Myeloperoxidase induces monocyte migration and activation after acute myocardial infarction.

Introduction: Myocardial infarction (MI) is a significant contributor to morbidity and mortality worldwide. Many individuals who survive the acute event continue to experience heart failure (HF), with inflammatory and healing processes post-MI playing a pivotal role. Polymorphonuclear neutrophils (PMN) and monocytes infiltrate the infarcted area, where PMN release high amounts of the heme enzyme myeloperoxidase (MPO).

Remodeling of the endothelial cell transcriptional program via paracrine and DNA-binding activities of MPO.

Myeloperoxidase (MPO) is an enzyme that functions in host defense. MPO is released into the vascular lumen by neutrophils during inflammation and may adhere and subsequently penetrate endothelial cells (ECs) coating vascular walls. We show that MPO enters the nucleus of ECs and binds chromatin independently of its enzymatic activity.