Single‐Cell Sequencing in the Genetic Model of Mitochondrial Dysfunction Reveals Heterogeneity of Lung Endothelial Cells and Novel Targets in Pulmonary Hypertension

Decision letter: Single-cell transcriptomic atlas of lung microvascular regeneration after targeted endothelial cell ablation

To be EndMT or not to be, that is the question in pulmonary hypertension.

Commentary: Mitochondrial respiration in right heart failure

Drug Therapy for Pulmonary Arterial Hypertension: What's on the Menu Today?

Sildenafil for Pulmonary Arterial Hypertension: Exciting, But Protection Required

Right ventricular (RV) function is the predominant determinant of survival in patients with pulmonary arterial hypertension (PAH). In preclinical models, pharmacological activation of BMP (bone morphogenetic protein) signaling with FK506 (tacrolimus) improved RV function by decreasing RV afterload. FK506 therapy further stabilized three patients with end-stage PAH. Whether FK506 has direct effects on the pressure-overloaded right ventricle is yet unknown. We hypothesized that increasing cardiac BMP signaling with FK506 improves RV structure and function in a model of fixed RV afterload after pulmonary artery banding (PAB). Direct cardiac effects of FK506 on the microvasculature and RV fibrosis were studied after surgical PAB in wild-type and heterozygous Bmpr2 mutant mice. RV function and strain were assessed longitudinally via cardiac magnetic resonance imaging during continuous FK506 infusion. Genetic lineage tracing of endothelial cells (ECs) was performed to assess the contribution of ECs to fibrosis. Molecular mechanistic studies were performed in human cardiac fibroblasts and ECs. In mice, low BMP signaling in the right ventricle exaggerated PAB-induced RV fibrosis. FK506 therapy restored cardiac BMP signaling, reduced RV fibrosis in a BMP-dependent manner independent from its immunosuppressive effect, preserved RV capillarization, and improved RV function and strain over the time course of disease. Endothelial mesenchymal transition was a rare event and did not significantly contribute to cardiac fibrosis after PAB. Mechanistically, FK506 required ALK1 in human cardiac fibroblasts as a BMPR2 co-receptor to reduce TGFβ1-induced proliferation and collagen production. Our study demonstrates that increasing cardiac BMP signaling with FK506 improves RV structure and function independent from its previously described beneficial effects on pulmonary vascular remodeling.

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Comprehensive Assessment of Right Ventricular Function in Patients with Pulmonary Hypertension with Global Longitudinal Peak Systolic Strain Derived from Multiple Right Ventricular Views

Right ventricular dysfunction in heart failure with reduced vs. preserved ejection fraction: non-identical twins?

Does Glycine cataBOLAsm Drive Pulmonary Hypertension?

Impaired right ventricular function and elevated pulmonary artery pressure: a lethal combination

Circulating Angiogenic Precursors in Idiopathic Pulmonary Arterial Hypertension

Second International Pulmonary Hypertension/Heart Failure Symposium—Structural heart disease, right ventricular dysfunction, and stem cell therapy: The European Pediatric Pulmonary Vascular Disease Network

Pulmonary arterial hypertension (PAH) is a syndrome in which pulmonary arterial obstruction increases pulmonary vascular resistance, which leads to right ventricular (RV) failure and a 15% annual mortality rate. The present review highlights recent advances in the basic science of PAH. New concepts clarify the nature of PAH and provide molecular blueprints that explain how PAH is initiated and maintained. Five basic science concepts provide a framework to understand and treat PAH: (1) Endothelial dysfunction creates an imbalance that favors vasoconstriction, thrombosis, and mitogenesis. Restoration of this balance by inhibition of endothelin and thromboxane or augmentation of nitric oxide (NO) and prostacyclin is the paradigm on which most current therapy is based. (2) PAH has a genetic component. Mutations (bone morphogenetic protein receptor-2 [BMPR2]) and single-nucleotide polymorphisms (SNPs; ion channels and transporter genes) predispose to PAH. (3) Excess proliferation, impaired apoptosis, and glycolytic metabolism in pulmonary artery smooth muscle, fibroblasts, and endothelial cells suggest analogies to cancer. Many experimental therapies reduce PAH by decreasing the proliferation/apoptosis ratio; these include inhibitors of pyruvate dehydrogenase kinase (PDK), serotonin transporters (SERT), survivin, 3-hydroxy-3-methylglutaryl coenzyme A reductase, transcription factors (hypoxia-inducible factor [HIF]-1α and nuclear factor of activated T lymphocytes [NFAT]), and tyrosine kinases. Augmentation of voltage-gated K+ channels (Kv1.5) and BMPR2 signaling also addresses this imbalance. Tyrosine kinase inhibitors used to treat cancer are currently in phase 1 PAH trials. (4) Refractory vasoconstriction may occur due to rho kinase activation. Fewer than 20% of PAH patients respond to conventional vasodilators; however, refractory vasoconstriction may respond to rho kinase inhibitors. (5) The RV can be targeted therapeutically. Although increased afterload initiates RV failure, which is the major cause of death/dysfunction in PAH, the RV may be amenable to cardiac-targeted therapies. The RV in PAH has features of ischemic, hibernating myocardium. Guided by these new …

pulmonary hypertension (PH), diagnosed when mean pulmonary arterial pressure exceeds the upper limits of normal (i.e., >25 mmHg) at rest (2), occurs in a variety of clinical situations and is associated with a broad spectrum of histological patterns and abnormalities. PH is currently classified into five distinct World Health Organization (WHO) groups, based on common clinical parameters, potential etiological mechanisms, and responses to treatment (22). Although any form of PH can contribute to increased patient morbidity and mortality, pulmonary arterial hypertension (PAH) (WHO group 1) is a particularly severe and progressive form associated with right heart failure and premature death (1). At present, therapeutic approaches to stabilize or reverse this debilitating condition involve treatment with one or a combination of up to three specific classes of agents, including prostacyclin analogs, endothelin-1 receptor antagonists, and/or phosphodiesterase-5 inhibitors. Retrospective (meta)analyses of these therapeutic strategies have demonstrated a reduction in mortality with their use (7, 12); however, many experts believe that current PAH treatment is inadequate given the persistently high mortality rate and functional hemodynamic impairment in many patients. These observations have led to continued intensive investigation into pathogenetic mechanisms and many proposals for additional alternative new therapies (20, 24). Among the potential new therapies, increasing interest in the role of endothelial progenitor cells (EPCs) as a cell-based therapy has emerged. However, issues remain regarding what group of PH patients are most likely to benefit from treatment, at what point in the disease is treatment most likely to be successful, and what types of cells should be utilized for therapy.