The Role of the Redox Enzyme p66Shc in Biological Aging of the Lung.

The mitochondrial adaptor protein p66Shc has been suggested to control life span in mice via the release of hydrogen peroxide. However, the role of p66Shc in lung aging remains unsolved. Thus, we investigated the effects of p66Shc on the aging of the lung and pulmonary circulation.

Decreased plasma levels of the brain-derived neurotrophic factor correlate with right heart congestion in pulmonary arterial hypertension.

Background: The brain-derived neurotrophic factor (BDNF) may promote development of pulmonary hypertension and right ventricular (RV) failure. However, BDNF plasma levels were decreased in patients with left ventricular (LV) failure. Therefore, we investigated BDNF plasma levels in pulmonary hypertension patients and the role of BDNF in mouse models of pulmonary hypertension and isolated RV failure.

Impairment of hypoxic pulmonary vasoconstriction in acute respiratory distress syndrome.

Acute respiratory distress syndrome (ARDS) is a serious complication of severe systemic or local pulmonary inflammation, such as caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. ARDS is characterised by diffuse alveolar damage that leads to protein-rich pulmonary oedema, local alveolar hypoventilation and atelectasis. Inadequate perfusion of these areas is the main cause of hypoxaemia in ARDS.

Genetic deletion of p66shc and/or cyclophilin D results in decreased pulmonary vascular tone.

Aims: The pulmonary vascular tone and hypoxia-induced alterations of the pulmonary vasculature may be regulated by the mitochondrial membrane permeability transition pore (mPTP) that controls mitochondrial calcium load and apoptosis. We thus investigated, if the mitochondrial proteins p66shc and cyclophilin D (CypD) that regulate mPTP opening affect the pulmonary vascular tone.

Methods And Results: Mice deficient for p66shc (p66shc-/-), CypD (CypD-/-), or both proteins (p66shc/CypD-/-) exhibited decreased pulmonary vascular resistance (PVR) compared to wild-type mice determined in isolated lungs and in vivo.

Amelioration of elastase-induced lung emphysema and reversal of pulmonary hypertension by pharmacological iNOS inhibition in mice.

Background And Purpose: Chronic obstructive pulmonary disease, encompassing chronic airway obstruction and lung emphysema, is a major worldwide health problem and a severe socio-economic burden. Evidence previously provided by our group has shown that inhibition of inducible NOS (iNOS) prevents development of mild emphysema in a mouse model of chronic tobacco smoke exposure and can even trigger lung regeneration. Moreover, we could demonstrate that pulmonary hypertension is not only abolished in cigarette smoke-exposed iNOS mice but also precedes emphysema development.

Impact of the mitochondria-targeted antioxidant MitoQ on hypoxia-induced pulmonary hypertension.

Increased mitochondrial reactive oxygen species (ROS), particularly superoxide, have been suggested to mediate hypoxic pulmonary vasoconstriction (HPV), chronic hypoxia-induced pulmonary hypertension and right ventricular remodelling.We determined ROS in acute and chronic hypoxia, and investigated the effect of the mitochondria-targeted antioxidant MitoQ under these conditions.The effect of MitoQ or its inactive carrier substance, decyltriphenylphosphonium, on acute HPV (1% O for 10 min) was investigated in isolated blood-free perfused mouse lungs.

Mitochondrial Complex IV Subunit 4 Isoform 2 Is Essential for Acute Pulmonary Oxygen Sensing.

Rationale: Acute pulmonary oxygen sensing is essential to avoid life-threatening hypoxemia via hypoxic pulmonary vasoconstriction (HPV) which matches perfusion to ventilation. Hypoxia-induced mitochondrial superoxide release has been suggested as a critical step in the signaling pathway underlying HPV. However, the identity of the primary oxygen sensor and the mechanism of superoxide release in acute hypoxia, as well as its relevance for chronic pulmonary oxygen sensing, remain unresolved.

Effects of carbon monoxide-releasing molecules on pulmonary vasoreactivity in isolated perfused lungs.

In addition to its renowned poisonous effects, carbon monoxide (CO) is being recognized for its beneficial actions on inflammatory and vasoregulatory pathways, particularly when applied at low concentrations via CO-releasing molecules (CO-RMs). In the lung, CO gas and CO-RMs are suggested to decrease pulmonary vascular tone and hypoxic pulmonary vasoconstriction (HPV). However, the direct effect of CO-RMs on the pulmonary vasoreactivity in isolated lungs has not yet been investigated.

Effects of dimethylarginine dimethylaminohydrolase-1 overexpression on the response of the pulmonary vasculature to hypoxia.

Acute and sustained hypoxic pulmonary vasoconstriction (HPV), as well as chronic pulmonary hypertension (PH), is modulated by nitric oxide (NO). NO synthesis can be decreased by asymmetric dimethylarginine (ADMA), which is degraded by dimethylarginine dimethylaminohydrolase-1 (DDAH1). We investigated the effects of DDAH1 overexpression (DDAH1(tg)) on HPV and chronic hypoxia-induced PH.