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Redox and Inflammatory Signaling, the Unfolded Protein Response, and the Pathogenesis of Pulmonary Hypertension

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Lung Inflammation in Health and Disease, Volume II

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1304))

Abstract

Protein folding overload and oxidative stress disrupt endoplasmic reticulum (ER) homeostasis, generating reactive oxygen species (ROS) and activating the unfolded protein response (UPR). The altered ER redox state induces further ROS production through UPR signaling that balances the cell fates of survival and apoptosis, contributing to pulmonary microvascular inflammation and dysfunction and driving the development of pulmonary hypertension (PH). UPR-induced ROS production through ER calcium release along with NADPH oxidase activity results in endothelial injury and smooth muscle cell (SMC) proliferation. ROS and calcium signaling also promote endothelial nitric oxide (NO) synthase (eNOS) uncoupling, decreasing NO production and increasing vascular resistance through persistent vasoconstriction and SMC proliferation. C/EBP-homologous protein further inhibits eNOS, interfering with endothelial function. UPR-induced NF-κB activity regulates inflammatory processes in lung tissue and contributes to pulmonary vascular remodeling. Conversely, UPR-activated nuclear factor erythroid 2-related factor 2-mediated antioxidant signaling through heme oxygenase 1 attenuates inflammatory cytokine levels and protects against vascular SMC proliferation. A mutation in the bone morphogenic protein type 2 receptor (BMPR2) gene causes misfolded BMPR2 protein accumulation in the ER, implicating the UPR in familial pulmonary arterial hypertension pathogenesis. Altogether, there is substantial evidence that redox and inflammatory signaling associated with UPR activation is critical in PH pathogenesis.

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Abbreviations

Ang II:

Angiotensin II

AP-1:

Activator protein 1

APx:

Ascorbate peroxidase

ARE:

Antioxidant response element

ASC:

Apoptosis-associated speck-like protein containing a CARD

ASK1:

Apoptosis signal-regulating kinase 1

ATF:

Activating transcription factor

ATFS-1:

Activating transcription factor associated with stress 1

Bach1:

BTB and CNC homology 1

BAK:

BCL-2 homologous antagonist/killer

BAX:

BCL-2-associated X protein

BBF2H7:

Box B-binding factor 2 human homolog on chromosome 7

BCL-2:

B cell lymphoma 2

BH3:

BCL-2 homology 3

BH4:

Tetrahydrobiopterin

BIM:

BCL-2-interacting mediator of cell death

BiP:

Immunoglobulin binding protein

BMPR2:

Bone morphogenic protein type 2 receptor

BPA:

Bovine pulmonary artery

bZIP:

Basic leucine zipper

C/EBP:

CCAAT/enhancer-binding protein

CaMKII:

Calcium/calmodulin-dependent kinase II

CHOP:

C/EBP-homologous protein

CO:

Carbon monoxide

COMP:

Cartilage oligomeric matrix protein

COPII:

Coat protein II

CRE:

Cyclic AMP response element

DAMP:

Damage-associated molecular pattern

EC:

Endothelial cell

ECM:

Extracellular matrix

eIF2α:

Eukaryotic translation initiation factor 2α

EndMT:

Endothelial-mesenchymal transition

eNOS:

Endothelial nitric oxide synthase

EPC:

Endothelial progenitor cell

ER:

Endoplasmic reticulum

ERAD:

ER-associated degradation

ERK:

Extracellular signal-regulated kinase

ERO1:

ER oxidoreductase 1

ERSE:

ER stress response element

ET-1:

Endothelin-1

FAD:

Flavin adenine dinucleotide

FPAH:

Familial pulmonary arterial hypertension

GADD34:

Growth arrest and DNA damage-inducible 34

GAG:

Glycosaminoglycan

GCLC:

Glutamate-cysteine ligase catalytic subunit

GCN2:

General control nonderepressible 2

GM-CSF:

Granulocyte-macrophage colony-stimulating factor

GPx7/8:

Glutathione peroxidase 7 and 8

GR:

Glutathione reductase

GSH/GSSG:

Glutathione (reduced/oxidized)

GSH1:

γ-glutamylcysteine synthetase

GST:

Glutathione S-transferase

H/R:

Hypoxia/ischemia and reoxygenation

H2O2:

Hydrogen peroxide

HA:

Hyaluronan

HDAC4:

Histone deacetylase 4

HIFα:

Hypoxia-inducible factor α

HIV-PAH:

HIV-induced pulmonary arterial hypertension

HO-1:

Heme oxygenase 1

HOCl:

Hypochlorous acid

HPAEC:

Human pulmonary arterial endothelial cell

HPMEC:

Human pulmonary microvascular endothelial cell

HRE:

Hypoxia response element

HSP47:

Heat shock protein 47

IKK:

Inhibitor of nuclear factor-κB (IκB) kinase

IL:

Interleukin

IP3R:

Inositol 1,4,5-triphosphate receptor

IRE1:

Inositol-requiring protein 1

ISR:

Integrated stress response

IκB:

Inhibitor of nuclear factor-κB

JNK:

JUN N-terminal kinase

KEAP1:

Kelch-like ECH-associated protein 1

LC20:

20-kDa regulatory light chain of myosin II

LPS:

Lipopolysaccharide

MA:

Methamphetamine

Maf:

Musculoaponeurotic fibrosarcoma

MAM:

Mitochondria-associated membrane

MAPK:

Mitogen-activated protein kinase

MCP:

Monocyte chemoattractant protein

MCT:

Monocrotaline

Mdm2:

Mouse double minute 2 homolog

MEF:

Myocyte enhancer factor

MIP:

Macrophage inflammatory protein

MLCK:

Myosin light chain kinase

MMP:

Matrix metalloproteinase

NAD:

Nicotine adenine dinucleotide

NF-Y:

Nuclear transcription factor Y

NF-κB:

Nuclear factor kappa-light-chain-enhancer of activated B cells

NIK:

NF-κB inducing kinase

NLRP3:

Nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) family, leucine-rich repeat (LRR), and pyrin domain (PYD)-containing protein-3

NO:

Nitric oxide

NOX:

NADPH oxidase

NQO1:

NAD(P)H: quinone oxidoreductase 1

NRF2:

Nuclear factor erythroid 2-related factor 2

O2:

Oxygen

OASIS:

Old astrocyte specifically induced substance

PAEC:

Pulmonary arterial endothelial cell

PAH:

Pulmonary arterial hypertension

PAMP:

Pathogen-associated molecular pattern

PASMC:

Pulmonary artery smooth muscle cell

PCNA:

Proliferating cell nuclear antigen

PDI:

Protein disulfide isomerase

PERK:

Protein kinase RNA-like endoplasmic reticulum kinase

PH:

Pulmonary hypertension

PHD:

Proline hydroxylase

PI3K:

Phosphoinositide-3 kinase

PKB:

Protein kinase B

PKC:

Protein kinase C

PP1C:

Protein phosphatase 1C

PRxIV:

Peroxiredoxin IV

PTP:

Permeability transition pore

PUMA:

p53 upregulated modulator of apoptosis

QSOX:

Quiescin sulfhydryl oxidase

RHAMM:

Receptor for HA-mediated motility

RIDD:

Regulated IRE1-dependent decay

ROS:

Reactive oxygen species

RVSP:

Right ventricle systolic pressure

S1P:

Site 1 protease

S2P:

Site 2 protease

SFN:

Sulforaphane

SMC:

Smooth muscle cell

SOD:

Superoxide dismutase

SRXN-1:

Sulfiredoxin-1

Tat:

Trans-activator of transcription

TGFβ:

Transforming growth factor β

TIM:

Translocase of the inner membrane

TLR:

Toll-like receptor

TNF-α:

Tumor necrosis factor α

TOM:

Translocase of the outer membrane

TRAF:

Tumor necrosis factor receptor-associated factor

Treg:

Regulatory T cell

TRx:

Thioredoxin

TXNIP:

TRx interacting protein

UGT:

UDP glucuronosyl transferase

UPR:

Unfolded protein response

UPRam:

UPR activated by protein mistargeting

UPRmt:

Mitochondrial UPR

UPS:

Ubiquitin-proteasome system

VDCC:

Voltage-dependent calcium channel

VHL:

Von Hippel-Lindau

VKOR:

Vitamin K epoxide reductase

VPO1:

Vascular peroxidase 1

XBP1:

X-box binding protein 1

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Acknowledgment

Recent studies from our lab have been funded by NIH grants R01HL115124, R01129797, and R01HL151187.

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Authors and Affiliations

  1. Department of Microbiology and Immunology, New York Medical College, Valhalla, NY, USA

    Adiya Katseff

  2. Department of Physiology, New York Medical College, Valhalla, NY, USA

    Raed Alhawaj & Michael S. Wolin

  3. Department of Physiology, Faculty of Medicine, Kuwait University, Safat, Kuwait

    Raed Alhawaj

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  1. Adiya Katseff
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  2. Raed Alhawaj
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  3. Michael S. Wolin
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Correspondence to Michael S. Wolin .

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  1. Department of Molecular & Cellular Physiology, Albany Medical College, Albany, NY, USA

    Yong-Xiao Wang

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Katseff, A., Alhawaj, R., Wolin, M.S. (2021). Redox and Inflammatory Signaling, the Unfolded Protein Response, and the Pathogenesis of Pulmonary Hypertension. In: Wang, YX. (eds) Lung Inflammation in Health and Disease, Volume II. Advances in Experimental Medicine and Biology, vol 1304. Springer, Cham. https://doi.org/10.1007/978-3-030-68748-9_17

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