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Cross Talk Between Mitochondrial Reactive Oxygen Species and Sarcoplasmic Reticulum Calcium in Pulmonary Arterial Smooth Muscle Cells

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Pulmonary Vasculature Redox Signaling in Health and Disease

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 967))

Abstract

Hypoxic pulmonary vasoconstriction (HPV) occurs during both fetal and postnatal development and plays a critical role in matching regional alveolar perfusion with ventilation in humans and animals. HPV also contributes significantly to the development of pulmonary hypertension. Although the molecular mechanisms of HPV and pulmonary hypertension remain incompletely understood, increasing evidence demonstrates that hypoxia induces an elevated intracellular reactive oxygen species concentration ([ROS]i) in pulmonary artery smooth muscle cells (PASMCs). The increased [ROS]i is attributed to the mitochondrial electron transport chain (ETC) and plasmalemmal NADPH oxidase (NOX); however, the mitochondrial ETC is a primary source for the elevated [ROS]i. Our studies reveal that mitochondrial ROS can specifically increase the activity of protein kinase C-ε, activate NOX, and then induce more ROS production (i.e., ROS-induced ROS production, RIRP). Mitochondrial ROS production is principally mediated by Rieske iron–sulfur protein (RISP) at the complex III. The increased [ROS]i causes an elevation of intracellular Ca2+ concentration ([Ca2+]i), thereby leading to HPV and associated pulmonary hypertension. Ryanodine receptor-2 (RyR2)/Ca2+ release channel on the sarcoplasmic reticulum (SR) serves as a most valuable player in the elevated [Ca2+]i. Our recent data indicate that RyR2-induced Ca2+ release can enhance RISP-mediated increase in mitochondrial ROS concentration ([ROS]mito), and that the mitochondrial Ca2+ uniporter is involved in elevating [ROS]mito. Based on the existing reports and our unpublished data, we conclude that the cross talk between [ROS]mito and [Ca2+]i, that is RISP-dependent mitochondrial ROS-induced RyR2-mediated SR Ca2+ release (ROS-induced Ca2+ release, RICR) and RyR2-mediated SR Ca2+ release-induced RISP-dependent mitochondrial ROS production (Ca2+-induced ROS production, CIRP), may form a positive reciprocal loop in mediating HPV and also possibly pulmonary hypertension.

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Abbreviations

[Ca2+]i :

Intracellular Ca2+ concentration

[Ca2+]mito :

Intramitochondrial Ca2+ concentration

[ROS]i :

Intracellular ROS concentration

[ROS]mito :

Intramitochondrial ROS concentration

BSO:

Buthionine sulfoximine

CIRP:

Ca2+-induced ROS production

COPD:

Chronic obstructive pulmonary disease

DAG:

Diacylglycerol

ER/SR:

Endoplasmic reticulum/sarcoplasmic reticulum

ETC:

Electron transport chain

HPV:

Hypoxic pulmonary vasoconstriction

IP3 :

Inositol 1,4,5-trisphosphate

IP3R:

Inositol 1,4,5-trisphosphate receptor

MCU:

Mitochondrial Ca2+ uniporter

MEFs:

Mouse embryonic fibroblasts

NOX:

NADPH oxidase

PASMCs:

Pulmonary arterial smooth muscle cells

PKC:

Protein kinase C

RICR:

ROS-induced Ca2+ release

RIPR:

ROS-induced ROS production

RISP:

Rieske iron–sulfur protein

ROCK:

Rho kinase

ROS:

Reactive oxygen species

RyR2:

Ryanodine receptor 2

SOCC:

Store operated Ca2+ channel

SOD:

Superoxide dismutase

STIM:

Stromal interaction molecule

TRPC:

Canonical transient receptor potential

TRPV:

Vanilloid transient receptor potential

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Acknowledgement

We thank Ms. Sudeshna Sadhu and Mr. Vic Maietta for proofreading of this chapter.

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Authors and Affiliations

  1. Department of Molecular and Cellular Physiology, Albany Medical College, 47 New Scotland Avenue (MC-8), Albany, NY, 12208, USA

    Tengyao Song, Yun-Min Zheng & Yong-Xiao Wang

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  1. Tengyao Song
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Correspondence to Yun-Min Zheng or Yong-Xiao Wang .

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  1. Department of Molecular and Cellular Physiology, Albany Medical College, Albany, New York, USA

    Yong-Xiao Wang

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Song, T., Zheng, YM., Wang, YX. (2017). Cross Talk Between Mitochondrial Reactive Oxygen Species and Sarcoplasmic Reticulum Calcium in Pulmonary Arterial Smooth Muscle Cells. In: Wang, YX. (eds) Pulmonary Vasculature Redox Signaling in Health and Disease. Advances in Experimental Medicine and Biology, vol 967. Springer, Cham. https://doi.org/10.1007/978-3-319-63245-2_17

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