Increased Mutagen Sensitivity and DNA Damage in Pulmonary Arterial Hypertension

Background: Right ventricular failure (RVF) is a poor prognostic factor for pulmonary arterial hypertension (PAH) patients. Inflammation, oxidative stress-induced DNA damage, and glycolysis are key RVF-driven pathways triggering cardiomyocytes (CM) dysfunction. Persistent DNA damage-dependent Poly (ADP ribose) Polymerase 1 (PARP1) activation was documented to promote glycolysis and pro-inflammatory responses through nuclear retention of Pyruvate Kinase Muscle isozyme 2 (PKM2). Despite the tremendous attention to PARP1/PKM2 axis in many pathologies, their implication in RVF remains unexplored. We hypothesized sustained PARP1 activation accounts for nuclear PKM2 localization, contributing to CM dysfunction and transition from compensated (cRVH) to decompensated RVH(dRVH). Methods and Results: We found by WB and IF that PARP1/PKM2 expression/activity is increased in dRVH (patients died from RVF, n=9) compared to cRVH (Cardiac index >2.2, n=14) and control donors (n=14) and correlates with RV hypertrophy and fibrosis. Similar findings were found in two rat models of RVF (monocrotaline; MCT, pulmonary artery banding; PAB). In addition, cardiac inflammation (NF-kB, HMGB1, IL-8, CCL-2, SOCS3, CD68), oxidative DNA damage (MTH1, 8-oxodG), and apoptosis (TUNEL) were significantly increased in dRVH compared to cRVH (human and rat models). In vitro , we confirmed by WB and IF that oxidative DNA damage (H 2 O 2 ) induce nuclear expression of PARP1/PKM2 in CM leading to the release of inflammatory mediators (NFkB, HMGB1) and cell death. These effects were prevented by pharmacological inhibition of PARP1 (ABT888) and enforced cytosolic retention of PKM2 (TEPP46 and DASA58). In vivo , PARP1 inhibition (Olaparib; 10mg/kg) as well as TEPP46 (25mg/kg) delayed progression of RVF (CO, hypertrophy, fibrosis, inflammation, DNA damage, apoptosis) in PAB rats (n=8 per groups). Preliminary data indicate CM-specific inactivation of PARP1 induces resistance to RVF in PAB mice (All p<0.05). Conclusions: We demonstrated for the first time that PARP1/PKM2 axis is a critical integrator of oxidative stress, inflammation, and metabolic dysfunction during pathological RVF. Modulating PARP1/PKM2 axis may represent a promising avenue for ameliorating RVF in PAH.

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DNA Damage and Repair in Pulmonary Arterial Hypertension

Genes ◽

10.3390/genes11101224 ◽

2020 ◽

Vol 11 (10) ◽

pp. 1224

Author(s):

Samantha Sharma ◽

Micheala A. Aldred

Keyword(s):

Dna Damage ◽

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Dna Damage Response ◽

Dna Damage And Repair ◽

Damage Response ◽

Different Types ◽

Pulmonary Arterial ◽

Novel Therapeutic Strategies ◽

Made In

Pulmonary arterial hypertension (PAH) is a complex multifactorial disease with both genetic and environmental dynamics contributing to disease progression. Over the last decade, several studies have demonstrated the presence of genomic instability and increased levels of DNA damage in PAH lung vascular cells, which contribute to their pathogenic apoptosis-resistant and proliferating characteristics. In addition, the dysregulated DNA damage response pathways have been indicated as causal factors for the presence of persistent DNA damage. To understand the significant implications of DNA damage and repair in PAH pathogenesis, the current review summarizes the recent advances made in this field. This includes an overview of the observed DNA damage in the nuclear and mitochondrial genome of PAH patients. Next, the irregularities observed in various DNA damage response pathways and their role in accumulating DNA damage, escaping apoptosis, and proliferation under a DNA damaging environment are discussed. Although the current literature establishes the pertinence of DNA damage in PAH, additional studies are required to understand the temporal sequence of the above-mentioned events. Further, an exploration of different types of DNA damage in conjunction with associated impaired DNA damage response in PAH will potentially stimulate early diagnosis of the disease and development of novel therapeutic strategies.

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Poly ADP‐Ribose polymerase (PARP‐1) and DNA damage in pulmonary arterial hypertension

The FASEB Journal ◽

10.1096/fasebj.27.1_supplement.1140.17 ◽

2013 ◽

Vol 27 (S1) ◽

Author(s):

Jolyane Meloche ◽

Audrey Courboulin ◽

Jana Krietsch ◽

Guillaume Margaillan ◽

Antony Courchesne ◽

...

Keyword(s):

Dna Damage ◽

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Pulmonary Arterial ◽

Parp 1

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Role for DNA Damage Signaling in Pulmonary Arterial Hypertension

Circulation ◽

10.1161/circulationaha.113.006167 ◽

2014 ◽

Vol 129 (7) ◽

pp. 786-797 ◽

Cited By ~ 128

Author(s):

Jolyane Meloche ◽

Aude Pflieger ◽

Mylène Vaillancourt ◽

Roxane Paulin ◽

François Potus ◽

...

Keyword(s):

Dna Damage ◽

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Dna Damage Signaling ◽

Pulmonary Arterial

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Inducing Oxidative DNA Damage Overload by Inhibiting the 8oxoguanine Hydrolase MTH1 to Kill Pulmonary Artery Smooth Muscle Cells: A New Therapeutic Strategy in Pulmonary Arterial Hypertension

10.1164/ajrccm-conference.2019.199.1_meetingabstracts.a4192 ◽

2019 ◽

Author(s):

G. Vitry ◽

R. Paradis ◽

V. Nadeau ◽

E. Tremblay ◽

S. Provencher ◽

...

Keyword(s):

Dna Damage ◽

Smooth Muscle ◽

Pulmonary Arterial Hypertension ◽

Pulmonary Artery ◽

Arterial Hypertension ◽

Smooth Muscle Cells ◽

Oxidative Dna Damage ◽

Therapeutic Strategy ◽

Pulmonary Arterial ◽

Pulmonary Artery Smooth Muscle

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The DNA Damage Response and HIV-Associated Pulmonary Arterial Hypertension

International Journal of Molecular Sciences ◽

10.3390/ijms21093305 ◽

2020 ◽

Vol 21 (9) ◽

pp. 3305

Author(s):

Ari Simenauer ◽

Eva Nozik-Grayck ◽

Adela Cota-Gomez

Keyword(s):

Dna Damage ◽

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Dna Damage Response ◽

Regulatory Networks ◽

Cell Types ◽

Pulmonary Vasculature ◽

Increased Risk ◽

Damage Response ◽

Pulmonary Arterial

The HIV-infected population is at a dramatically increased risk of developing pulmonary arterial hypertension (PAH), a devastating and fatal cardiopulmonary disease that is rare amongst the general population. It is increasingly apparent that PAH is a disease with complex and heterogeneous cellular and molecular pathologies, and options for therapeutic intervention are limited, resulting in poor clinical outcomes for affected patients. A number of soluble HIV factors have been implicated in driving the cellular pathologies associated with PAH through perturbations of various signaling and regulatory networks of uninfected bystander cells in the pulmonary vasculature. While these mechanisms are likely numerous and multifaceted, the overlapping features of PAH cellular pathologies and the effects of viral factors on related cell types provide clues as to the potential mechanisms driving HIV-PAH etiology and progression. In this review, we discuss the link between the DNA damage response (DDR) signaling network, chronic HIV infection, and potential contributions to the development of pulmonary arterial hypertension in chronically HIV-infected individuals.

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