Egln1Tie2Cre Mice Exhibit Similar Therapeutic Responses to Sildenafil, Ambrisentan, and Treprostinil as Pulmonary Arterial Hypertension (PAH) Patients, Supporting Egln1Tie2Cre Mice as a Useful PAH Model
Abstract
Pulmonary arterial hypertension (PAH) is a progressive and inevitably fatal disease characterized by the progressive increase of pulmonary vascular resistance and obliterative pulmonary vascular remodeling, which lead to right-sided heart failure and premature death. Many of the genetically modified mouse models do not develop severe PH and occlusive vascular remodeling. Egln1Tie2Cre mice with Tie2Cre-mediated deletion of Egln1, which encodes hypoxia-inducible factor (HIF) prolyl hydroxylase 2 (PHD2), is the only mouse model with severe PAH, progressive occlusive pulmonary vascular remodeling, and right-sided heart failure leading to 50-80% mortality from the age of 3-6 months, indicating that the Egln1Tie2Cre mice model is a long-sought-after murine PAH model. However, it is unknown if Egln1Tie2Cre mice respond to FDA-approved PAH drugs in a way similar to PAH patients. Here, we tested the therapeutic effects of the three vasodilators: sildenafil (targeting nitric oxide signaling), ambrisentan (endothelin receptor antagonist), and treprostinil (prostacyclin analog) on Egln1Tie2Cre mice. All of them attenuated right ventricular systolic pressure (RVSP) in Egln1Tie2Cre mice consistent with their role as vasodilators. However, these drugs have no beneficial effects on pulmonary arterial function. Cardiac output was also markedly improved in Egln1Tie2Cre mice by any of the drug treatments. They only partially improved RV function and reduced RV hypertrophy and pulmonary…
Read the paper
Related studies
- Drug repositioning: a brief overview
- Cyclic nucleotide phosphodiesterases in Drosophila melanogaster
- Time-resolved in silico modeling of fine-tuned cAMP signaling in platelets: feedback loops, titrated phosphorylations and pharmacological modulation
- Current View on Green Tea Catechins Formulations, Their Interactions with Selected Drugs, and Prospective Applications for Various Health Conditions
- In silico Structure-based Identification of Novel Acetylcholinesterase Inhibitors Against Alzheimer’s Disease
- Development and In Vitro Evaluation of Controlled Release Viagra® Containing Poloxamer-188 Using Gastroplus™ PBPK Modeling Software for In Vivo Predictions and Pharmacokinetic Assessments
Go deeper in Evidence Hub
Evidence Hub adds a study data sheet (design, sample size, evidence level, key numbers), an AI summary and a chat grounded in the paper's text.