In:
Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 144, No. Suppl_1 ( 2021-11-16)
Abstract:
Introduction: Right ventricular (RV) function is the poor prognosis factor in pulmonary arterial hypertension (PAH) patients. Inflammation, oxidative DNA damage, and glycolysis are key triggering pathways that induce cardiomyocytes (CM) dysfunction. Oxidative DNA damage-dependent Poly (ADP ribose) Polymerase 1 (PARP1) activation was documented to promote glycolysis and inflammation through nuclear retention of Pyruvate Kinase Muscle isozyme 2 (PKM2). Despite PARP1/PKM2 axis is involved in many pathologies, their role in RV failure (RVF) remains unclear. We hypothesized that sustained PARP1 activation induces nuclear PKM2 localization, cardiac inflammation, and myocytes apoptosis resulting in transition from compensated (cRV) to decompensated RV (dRV). Methods and Results: We found that PARP1/PKM2 expression/activity (IF, WB) is upregulated in dRV patients (died of RVF, n=11) compared to cRV patients (CI 〉 2.2, n=12) and control donors (n=19). Similar findings were seen in two rat models of RVF (monocrotaline, PA banding). In vitro , we confirmed that oxidative DNA damage (ET-1+H 2 O 2 ) as well as inflammatory stress (ET-1+LPS) induced nuclear expression of PARP1/PKM2 (IF, WB) leading to inflammation (NF-κB nuclear translocation) and CM death (TUNEL). These effects were prevented by treatment with PARP1 inhibitor (ABT-888, Olaparib) or enforced cytosolic retention of PKM2 (TEPP-46, DASA-58). Cardiomyocytes isolated from neonatal Parp1 deficient mice were resistant to myocyte dysfunction (PKM2 nuclear upregulation, NF-κB nuclear translocation, TUNEL) induced by oxidative DNA damage (ET-1+H 2 O 2 ). In vivo , Olaparib (10mg/kg) as well as TEPP-46 (25mg/kg) prevented RVF (CO, hypertrophy, fibrosis, inflammation, DNA damage, apoptosis) induced by PAB in rats (n=8~12 per group). Moreover, we confirmed that global Parp1 loss-of-function confers protection against PAB induced-RVF (CO, hypertrophy, fibrosis, inflammation, DNA damage, apoptosis, n=10 per group). (All p 〈 0.05) Conclusions: We demonstrated for the first time that PARP1/PKM2 axis is a critical signal pathway RV decompensation. Targeting PARP1/PKM2 axis may represent a promising avenue for tackling maladaptive RV remodeling and pulmonary circulation, simultaneously.
Type of Medium:
Online Resource
ISSN:
0009-7322
,
1524-4539
DOI:
10.1161/circ.144.suppl_1.10231
Language:
English
Publisher:
Ovid Technologies (Wolters Kluwer Health)
Publication Date:
2021
detail.hit.zdb_id:
1466401-X
