Rieske Iron-Sulfur Protein Mediates Pulmonary Hypertension Following Nicotine/Hypoxia Coexposure.

The high mortality rate in patients with chronic obstructive pulmonary disease (COPD) may be due to pulmonary hypertension (PH). These diseases are highly associated with cigarette smoke and its key component nicotine. Here, we created a novel animal model of PH using coexposure to nicotine (or cigarette smoke) and hypoxia. This heretofore unreported model showed significant early-onset pulmonary vasoremodeling and PH. Using newly generated mice with complementary smooth muscle-specific Rieske iron-sulfur protein (RISP) gene knockout and overexpression, we demonstrate that RISP is critically involved in promoting pulmonary vasoremodeling and PH, which are implemented by oxidative ataxia telangiectasia-mutated-mediated DNA damage and NF-κB-dependent inflammation in a reciprocal positive mechanism. Together, our findings establish for the first time an animal model of hypoxia-induced early-onset PH in which mitochondrial RISP-dependent DNA damage and NF-κB inflammation play critical roles in vasoremodeling. Specific therapeutic targets for RISP and related oxidative stress-associated signaling pathways may create unique and effective treatments for PH, chronic obstructive pulmonary disease, and their complications.

The Potential Important Role of Mitochondrial Rieske Iron-Sulfur Protein as a Novel Therapeutic Target for Pulmonary Hypertension in Chronic Obstructive Pulmonary Disease.

Chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide, which is often due to pulmonary hypertension (PH). The underlying molecular mechanisms are poorly understood, and current medications are neither specific nor always effective. In this review, we highlight the recent findings on the roles of altered mitochondrial bioenergetics in PH in COPD. We also discuss the central role of mitochondrial reactive oxygen species (ROS) generation mediated by Rieske iron-sulfur protein (RISP) and review the contributions of RISP-dependent DNA damage and NF-κB-associated inflammatory signaling. Finally, the potential importance of mitochondrial RISP and its associated molecules as novel therapeutic targets for PH in COPD are meticulously discussed.

Overview on Interactive Role of Inflammation, Reactive Oxygen Species, and Calcium Signaling in Asthma, COPD, and Pulmonary Hypertension.

Inflammatory signaling is a major component in the development and progression of many lung diseases, including asthma, chronic obstructive pulmonary disorder (COPD), and pulmonary hypertension (PH). This chapter will provide a brief overview of asthma, COPD, and PH and how inflammation plays a vital role in these diseases. Specifically, we will discuss the role of reactive oxygen species (ROS) and Ca2+ signaling in inflammatory cellular responses and how these interactive signaling pathways mediate the development of asthma, COPD, and PH. We will also deliberate the key cellular responses of pulmonary arterial (PA) smooth muscle cells (SMCs) and airway SMCs (ASMCs) in these devastating lung diseases. The analysis of the importance of inflammation will shed light on the key questions remaining in this field and highlight molecular targets that are worth exploring. The crucial findings will not only demonstrate the novel roles of essential signaling molecules such as Rieske iron-sulfur protein and ryanodine receptor in the development and progress of asthma, COPD, and PH but also offer advanced insight for creating more effective and new therapeutic targets for these devastating inflammatory lung diseases.

Rieske iron-sulfur protein induces FKBP12.6/RyR2 complex remodeling and subsequent pulmonary hypertension through NF-κB/cyclin D1 pathway.

Ca2+ signaling in pulmonary arterial smooth muscle cells (PASMCs) plays an important role in pulmonary hypertension (PH). However, the underlying specific ion channel mechanisms remain largely unknown. Here, we report ryanodine receptor (RyR) channel activity and Ca2+ release both are increased, and association of RyR2 by FK506 binding protein 12.6 (FKBP12.6) is decreased in PASMCs from mice with chronic hypoxia (CH)-induced PH. Smooth muscle cell (SMC)-specific RyR2 knockout (KO) or Rieske iron-sulfur protein (RISP) knockdown inhibits the altered Ca2+ signaling, increased nuclear factor (NF)-κB/cyclin D1 activation and cell proliferation, and CH-induced PH in mice. FKBP12.6 KO or FK506 treatment enhances CH-induced PH, while S107 (a specific stabilizer of RyR2/FKBP12.6 complex) produces an opposite effect. In conclusion, CH causes RISP-dependent ROS generation and FKBP12.6/RyR2 dissociation, leading to PH. RISP inhibition, RyR2/FKBP12.6 complex stabilization and Ca2+ release blockade may be potentially beneficial for the treatment of PH.

Mitochondrial Rieske iron-sulfur protein in pulmonary artery smooth muscle: A key primary signaling molecule in pulmonary hypertension.

Rieske iron-sulfur protein (RISP) is a catalytic subunit of the complex III in the mitochondrial electron transport chain. Studies for years have revealed that RISP is essential for the generation of intracellular reactive oxygen species (ROS) via delicate signaling pathways associated with many important molecules such as protein kinase C-ε, NADPH oxidase, and ryanodine receptors. More significantly, mitochondrial RISP-mediated ROS production has been implicated in the development of hypoxic pulmonary vasoconstriction, leading to pulmonary hypertension, right heart failure, and death. Investigations have also shown the involvement of RISP in ROS-dependent cardiac ischemic/reperfusion injuries. Further research may provide novel and valuable information that can not only enhance our understanding of the functional roles of RISP and the underlying molecular mechanisms in the pulmonary vasculature and other systems, but also elucidate whether RISP targeting can act as preventative and restorative therapies against pulmonary hypertension, cardiac diseases, and other disorders.

Important Role of Sarcoplasmic Reticulum Ca2+ Release via Ryanodine Receptor-2 Channel in Hypoxia-Induced Rieske Iron-Sulfur Protein-Mediated Mitochondrial Reactive Oxygen Species Generation in Pulmonary Artery Smooth Muscle Cells.

Aims: It is known that mitochondrial reactive oxygen species generation ([ROS]m) causes the release of Ca2+via ryanodine receptor-2 (RyR2) on the sarcoplasmic reticulum (SR) in pulmonary artery smooth muscle cells (PASMCs), playing an essential role in hypoxic pulmonary vasoconstriction (HPV). In this study, we sought to determine whether hypoxia-induced RyR2-mediated Ca2+ release may in turn promote [ROS]m in PASMCs and the underlying signaling mechanism. Results: Our data reveal that application of caffeine or norepinephrine to induce Ca2+ release increased [ROS]m in PASMCs. Likewise, exogenous Ca2+ augmented ROS generation in isolated mitochondria and at complex III from PASMCs. Inhibition of mitochondrial Ca2+ uniporter (MCU) with Ru360 attenuated agonist-induced [ROS]m. Ru360 produced a similar inhibitory effect on hypoxia-induced [ROS]m. Rieske iron-sulfur protein (RISP) gene knockdown inhibited Ca2+- and caffeine-induced [ROS]m. Inhibition of RyR2 by tetracaine or RyR2 gene knockout suppressed hypoxia-induced [ROS]m as well. Innovation: In this article, we present convincing evidence that Ca2+ release following hypoxia or RyR simulation causes a significant increase in MCU, and the increased MCU subsequently RISP-dependent [ROS]m, which provides a positive feedback mechanism to enhance hypoxia-initiated [ROS]m in PASMCs. Conclusion: Our findings demonstrate that hypoxia-induced mitochondrial ROS-dependent SR RyR2-mediated Ca2+ release increases MCU and then RISP-dependent [ROS]m in PASMCs, which may make significant contributions to HPV and associated pulmonary hypertension.

Mitochondrial Rieske iron-sulfur protein in pulmonary artery smooth muscle: A key primary signaling molecule in pulmonary hypertension.

Rieske iron-sulfur protein (RISP) is a catalytic subunit of the complex III in the mitochondrial electron transport chain. Studies for years have revealed that RISP is essential for the generation of intracellular reactive oxygen species (ROS) via delicate signaling pathways associated with many important molecules such as protein kinase C-ε, NADPH oxidase, and ryanodine receptors. More significantly, mitochondrial RISP-mediated ROS production has been implicated in the development of hypoxic pulmonary vasoconstriction, leading to pulmonary hypertension, right heart failure, and death. Investigations have also shown the involvement of RISP in ROS-dependent cardiac ischemic/reperfusion injuries. Further research may provide novel and valuable information that can not only enhance our understanding of the functional roles of RISP and the underlying molecular mechanisms in the pulmonary vasculature and other systems, but also elucidate whether RISP targeting can act as preventative and restorative therapies against pulmonary hypertension, cardiac diseases, and other disorders.

Potential important roles and signaling mechanisms of YPEL4 in pulmonary diseases.

BACKGROUND: Human Yippee-like-4 (YPEL4) is a member of the YPEL gene family. This family has been characterized as the first highly conserved family of genes coding for proteins that contain putative zinc-finger-like metal-binding domains, known as the Yippee domain. The YPEL family proteins are located at the centrosome adjacent to the nucleolus during interphase and mitotic apparatus during mitosis. Due to its subcellular localization, it is believed that YPEL4 may have an important role in the cell cycle and proliferation. Recent studies have shown the involvement of YPEL4 in biological processes such as the mitogen-activated protein kinase pathway and adrenal cell proliferation. Research on YPEL4 up to date also suggests that YPEL4 is a very important player in pulmonary diseases. CONCLUSIONS: YPEL4 may regulate the mitogen-activated protein kinase signaling pathway to mediate adrenal cell proliferation; this molecule is also likely to be a very important player in pulmonary diseases. Although the function of YPEL4 is largely unknown, further research may substantiate the functional importance and underlying molecular processes in pulmonary and other diseases that would allow YPEL4 to become a therapeutic target.