Benoît Ranchoux

Background: Pulmonary hypertension (PH) due to left heart disease (PH-LHD) or Group2 PH is the most prevalent form of PH worldwide. PH-LHD is a deleterious complication of diastolic dysfunction and often associated with metabolic syndrome (MetS). The mechanisms remain unknown; PH-targeted therapies for this group are non-existent and the development of a new preclinical model is crucial. Inflammation plays a role in MetS, PH and adverse vascular remodeling. We hypothesized that MetS and inflammation may trigger the development of vascular remodeling in Group2 PH. Methods and results: In rats, we induced diastolic dysfunction by supra-coronary aortic banding (SAB) surgery and MetS, by the combination of a high-fat diet (HFD) and olanzapine. Only SAB+MetS rats developed precapillary PH (echocardiography and right/left heart catheterization). Lungs from Group2-PH patients and SAB+MetS rats displayed macrophage and IL-6 accumulation, STAT3 activation and increased proliferation of pulmonary artery smooth muscle cells (PASMC), which contributes to adverse remodeling of distal PA. In vitro, IL-6 activates STAT3 and induces pulmonary arterial smooth muscle cell proliferation. Metformin treatment decreased inflammation and IL-6 levels, and STAT3 activation and PASMC proliferation both. In vivo, targeting IL-6 by either anti-IL-6 antibody or metformin treatment reversed pulmonary vascular remodeling and improve PH-LHD. Conclusions: We developed a new preclinical model of Group 2 PH and showed that MetS exacerbates SAB-induced PH-LHD. We displayed that IL-6 promotes SAB-induced pulmonary vascular remodeling and PH-LHD. We proposed IL-6 as a therapeutic target in Groups 2 PH

The bromodomain and extra-terminal domain family inhibitors (BETi) are a promising new class of anticancer agents. Since numerous anticancer drugs have been correlated to cardiomyopathy, and since BETi can affect non-cancerous tissues, we aimed to investigate in healthy animals any ultrastructural BETi-induced alterations of the heart as compared to skeletal muscle. Male Wistar rats were either treated during 3 weeks with I-BET-151 (2 or 10 mg/kg/day) (W3) or treated for 3 weeks then allowed to recover for another 3 weeks (W6) (3-weeks drug washout). Male C57Bl/6J mice were only treated during 5 days (50 mg/kg/day). We demonstrated the occurrence of ultrastructural alterations and progressive destruction of cardiomyocyte mitochondria after I-BET-151 exposure. Those mitochondrial alterations were cardiac muscle-specific, since the skeletal muscles of exposed animals were similar in ultrastructure presentation to the non-exposed animals. I-BET-151 decreased the respiration rate of heart mitochondria in a dose-dependent manner. At the higher dose, it also decreased mitochondrial mass, as evidenced by reduced right ventricular citrate synthase content. I-BET-151 reduced the right and left ventricular fractional shortening. The concomitant decrease in the velocity-time-integral in both the aorta and the pulmonary artery is also suggestive of an impaired heart function. The possible context-dependent cardiac side effects of these drugs have to be appreciated. Future studies should focus on the basic mechanisms of potential cardiovascular toxicities induced by BETi and strategies to minimize these unexpected complications.

Endothelial dysfunction is a major player in the development and progression of vascular pathology in pulmonary arterial hypertension (PAH), a disease associated with small vessel loss and obstructive vasculopathy that leads to increased pulmonary vascular resistance, subsequent right heart failure, and premature death. Over the past ten years, there has been tremendous progress in our understanding of pulmonary endothelial biology as it pertains to the genetic and molecular mechanisms that orchestrate the endothelial response to direct or indirect injury, and how their dysregulation can contribute to the pathogenesis of PAH. As one of the major topics included in the 2017 Grover Conference Series, discussion centered on recent developments in four areas of pulmonary endothelial biology: (1) angiogenesis; (2) endothelial‐mesenchymal transition (EndMT); (3) epigenetics; and (4) biology of voltage‐gated ion channels. The present review will summarize the content of these discussions and provide a perspective on the most promising aspects of endothelial dysfunction that may be amenable for therapeutic development.

Pulmonary hypertension (PH) is defined by a mean pulmonary arterial pressure over 25 mmHg at rest and is diagnosed by right heart catheterization. Among the different groups of PH, pulmonary arterial hypertension (PAH) is characterized by a progressive obstruction of distal pulmonary arteries, related to endothelial cell dysfunction and vascular cell proliferation, which leads to an increased pulmonary vascular resistance, right ventricular hypertrophy, and right heart failure. Although the primary trigger of PAH remains unknown, oxidative stress and inflammation have been shown to play a key role in the development and progression of vascular remodeling. These factors are known to increase DNA damage that might favor the emergence of the proliferative and apoptosis-resistant phenotype observed in PAH vascular cells. High levels of DNA damage were reported to occur in PAH lungs and remodeled arteries as well as in animal models of PH. Moreover, recent studies have demonstrated that impaired DNA-response mechanisms may lead to an increased mutagen sensitivity in PAH patients. Finally, PAH was linked with decreased breast cancer 1 protein (BRCA1) and DNA topoisomerase 2-binding protein 1 (TopBP1) expression, both involved in maintaining genome integrity. This review aims to provide an overview of recent evidence of DNA damage and DNA repair deficiency and their implication in PAH pathogenesis.