Cystamine Treatment Fails to Prevent the Development of Pulmonary Hypertension in Chronic Hypoxic Rats.

Abstract

INTRODUCTION:

Pulmonary hypertension is characterized by vasoconstriction and remodeling of pulmonary arteries, leading to right ventricular hypertrophy and failure. We have previously found upregulation of transglutaminase 2 (TG2) in the right ventricle of chronic hypoxic rats. The hypothesis of the present study was that treatment with the transglutaminase inhibitor, cystamine, would inhibit the development of pulmonary arterial remodeling, pulmonary hypertension, and right ventricular hypertrophy.

METHODS:

Effect of cystamine on transamidase activity was investigated in tissue homogenates. Wistar rats were exposed to chronic hypoxia and treated with vehicle, cystamine (40 mg/kg/day in mini-osmotic pumps), sildenafil (25 mg/kg/day), or the combination for 2 weeks.

RESULTS:

Cystamine concentration-dependently inhibited TG2 transamidase activity in liver and lung homogenates. In contrast to cystamine, sildenafil reduced right ventricular systolic pressure and hypertrophy and decreased pulmonary vascular resistance and muscularization in chronic hypoxic rats. Fibrosis in the lung tissue decreased in chronic hypoxic rats treated with cystamine. TG2 expression was similar in the right ventricle and lung tissue of drug and vehicle-treated hypoxic rats.

DISCUSSION/CONCLUSIONS:

Cystamine inhibited TG2 transamidase activity, but cystamine failed to prevent pulmonary hypertension, right ventricular hypertrophy, and pulmonary arterial muscularization in the chronic hypoxic rat.

• Authors: Lars K Markvardsen, Lene D Sønderskov, Christine Wandall-Frostholm, Estéfano Pinilla, Judit Prat-Duran, Mathilde Aalling, Susie Mogensen, Charlotte U Andersen, Ulf Simonsen
• Journal: Journal of vascular research (J Vasc Res) Vol. 58 Issue 4 Pg. 237-251 ( 2021) ISSN: 1423-0135 [Electronic] Switzerland
• PMID: 33910208 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 S. Karger AG, Basel.

Chemical References

• Enzyme Inhibitors
• Tgm2 protein, rat
• Protein Glutamine gamma Glutamyltransferase 2
• Cystamine

Topics

• Animals
• Arterial Pressure (drug effects)
• Cystamine (pharmacology)
• Disease Models, Animal
• Enzyme Inhibitors (pharmacology)
• Female
• Hypertension, Pulmonary (enzymology, etiology, physiopathology, prevention & control)
• Hypertrophy, Right Ventricular (enzymology, etiology, physiopathology, prevention & control)
• Hypoxia (complications, drug therapy, enzymology, physiopathology)
• Male
• Mice, Inbred C57BL
• Protein Glutamine gamma Glutamyltransferase 2 (antagonists & inhibitors, metabolism)
• Pulmonary Artery (drug effects, enzymology, physiopathology)
• Pulmonary Fibrosis (enzymology, etiology, physiopathology, prevention & control)
• Rats, Wistar
• Vascular Remodeling (drug effects)
• Ventricular Function, Right (drug effects)
• Ventricular Remodeling (drug effects)