Lysanne M. Jorna, Dalibor Nakládal, Johannes N. van Heuveln, Diederik E. van der Feen, Quint A. J. Hagdorn, Guido P. L. Bossers, Annemieke van Oosten, Michel Weij, Ludmila Tkáciková, Sona Tkáciková, Robert H. Henning, Martin C. Harmsen, Rolf M. F. Berger, Guido Krenning
University Medical Center Groningen, University of Groningen. Comenius University Bratislava. University of Heidelberg. University of Veterinary Medicine and Pharmacy, Komenského. Pavol Jozef Šafárik University. Sulfateq B.V.
Netherlands, Slovakia and Germany
International Journal of Molecular Sciences
Int J Mol Sci 2025; 26:
DOI: 10.3390/ijms26157181
Abstract
Pulmonary arterial hypertension (PAH) is a rare, progressive, and incurable disease characterized by an elevated pulmonary blood pressure, extensive remodeling of the pulmonary vasculature, increased pulmonary vascular resistance, and culminating in right ventricular failure. Mitochondrial dysfunction has a major role in the pathogenesis of PAH and secondary right ventricular failure, and its targeting may offer therapeutic benefit. In this study, we provide proof-of-concept for the use of the mitochondrially active drug SUL-150 to treat PAH. PAH was induced in rats by monocrotaline, followed by the placement of an aortocaval shunt one week later. The mitoprotective compound SUL-150 (~6 mg·kg-1·day-1) or vehicle was administered intraperitoneally via osmotic minipump for 28 days, implanted at the time of aortocaval shunt placement. Vehicle-treated PAH rats had dyspnea and showed pulmonary artery remodeling with increased responsiveness to phenylephrine, in addition to remodeling of the intrapulmonary arterioles. SUL-150 administration mitigated the dyspnea and the remodeling responses. Vehicle-treated PAH rats developed right ventricular hypertrophy, fibrosis, and failure. SUL-150 administration precluded cardiomyocyte hypertrophy and inhibited ventricular fibrogenesis. Right ventricular failure in vehicle-treated PAH rats induced mitochondrial loss and dysfunction associated with a decrease in mitophagy. SUL-150 was unable to prevent the mitochondrial loss but improved mitochondrial health in the right ventricle, which culminated in the preservation of right ventricular function. We conclude that SUL-150 improves PAH-associated morbidity by the amelioration of pulmonary vascular remodeling and right ventricular failure and may be considered a promising therapeutic candidate to slow disease progression in pulmonary arterial hypertension and secondary right ventricular failure.
Category
Class I. Drug-induced and Toxin-induced Pulmonary Hypertension
Heart Dysfunction Associated with Pulmonary Vascular Disease (Right)
Animal Models of Pulmonary Vascular Disease and Therapy
Medical Therapy. Efficacy or Lack of Efficacy
Vascular Cell Biology and Mechanisms of Pulmonary Vascular Disease Animal Models of Pulmonary Vascular Disease and Therapy
Pulmonary Vascular Pathology
Age Focus: No Age-Related Focus
Fresh or Filed Publication: Fresh (PHresh). Less than 1-2 years since publication
Article Access
Free PDF File or Full Text Article Available Through PubMed or DOI: Yes