Macrophage–NLRP3 Activation Promotes Right Ventricle Failure in Pulmonary Arterial Hypertension

Abstract

Rationale: Pulmonary arterial hypertension (PAH) often results in death from right ventricular failure (RVF). NLRP3-macrophage activation may promote RVF in PAH. Objectives: Evaluating the contribution of the NLRP3 inflammasome in RV-macrophages to PAH-RVF. Methods: Rats with decompensated RV hypertrophy (RVH) [monocrotaline (MCT) and Sugen-5416 hypoxia (SuHx)] were compared with compensated RVH rats [pulmonary artery banding (PAB)]. Echocardiography and right heart catheterization were performed. Macrophages, atrial natriuretic peptide (ANP) and fibrosis were evaluated by microscopy or flow cytometry. NLRP3 inflammasome activation and cardiotoxicity were confirmed by immunoblot and in vitro strategies. MCT-rats were treated with SC-144 (a GP130 antagonist) and MCC950 (an NLRP3 inhibitor). Macrophage-NLRP3 activity was evaluated in PAH-RVF patients. Measurements and Main Results: Macrophages, fibrosis, and ANP were increased in MCT and SuHx-RVs but not LVs or PAB rats. While MCT-RV macrophages were inflammatory, lung macrophages were anti-inflammatory. CCR2 + macrophages (monocyte-derived) were increased in MCT-and SuHx-RVs and highly expressed NLRP3. The macrophage-NLRP3 pathway was upregulated in PAH patients' decompensated RVs. Cultured MCT-monocytes showed NLRP3 activation, and in co-culture experiments resulted in cardiomyocyte mitochondrial damage, which MCC950 prevented. In vivo, MCC950 reduced NLRP3 activation and regressed pulmonary vascular disease and RVF. SC-144 reduced RV-macrophages and NLRP3 content, prevented STAT3 activation, and improved RV function without regressing pulmonary vascular disease.

An integrated proteomic and transcriptomic signature of the failing right ventricle in monocrotaline induced pulmonary arterial hypertension in male rats

“…A recent meta-transcriptome paper demonstrated that this transcript is a robust biomarker for human heart failure progression in the left ventricle ( Hua et al, 2020 ). Although Collagen alpha III is known to be regulated at both the mRNA ( Potus et al, 2018 ) and the protein ( Al-Qazazi et al, 2022 ) level in the male RV of MCT induced rats, we did not observe Col3a1 protein changes in our proteomic data. We do not have data to determine whether this reflects an experimental issue (such as inadequate sample size) or a statistical false discovery issue.…”

“…These data in aggregate suggest that the MCT drug effect primarily impacts the RV rather than LV. Indeed, we have previously observed that the Nppa is expressed exclusively in the decompensated RV, but not the LV ( Al-Qazazi et al, 2022 ). We have reviewed the literature in an effort to identify compartment specific gene/protein expression, and reanalyzed the one available dataset where PAH was induced with MCT, and found that of the targets that map between platforms (microarray and RNAseq) ( Kittleson et al, 2005 ), none of our most robustly regulated RV genes were significantly regulated in that study of the LV.…”

“…These data in aggregate suggest that the MCT drug effect primarily impacts the RV rather than LV. Indeed, we have previously observed that the Nppa is expressed exclusively in the decompensated RV, but not the LV (Al-Qazazi et al, 2022).…”

Pulmonary Arterial Hypertension: Emerging Principles of Precision Medicine across Basic Science to Clinical Practice

“…Myeloid cell recruitment from bone marrow and blood has been highlighted as a key process in the development of vascular inflammation in PAH [140]. Furthermore, targeting right ventricular inflammation via the NLRP3 inflammasome has recently been described [141]. Correspondingly, circulating cytokine levels, including interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) are increased in PAH and correlate with mortality [142][143][144].…”

Misbehaving Guests in the Right Ventricle: Macrophage–NLRP3 Activation in Pulmonary Hypertension

“…In this issue of the Journal , Al-Qazazi and colleagues (pp. 608–624 ) test the hypothesis that RV inflammation, driven by activation of the NLRP3 inflammasome in recruited macrophages, is a contributor to RV maladaptive remodeling in experimental pulmonary hypertension ( 9 ). The authors demonstrate that M1-polarized, monocyte-derived, CCR2 + macrophages are increased in RVs (but not LVs) of rats with monocrotaline- or sugen/hypoxia-induced pulmonary hypertension and highly express NLRP3.…”