P21-dependent protective effects of a carbon monoxide-releasing molecule-3 in pulmonary hypertension.

Abstract

OBJECTIVE:

Carbon monoxide-releasing molecules (CORMs) represent a pharmacological alternative to CO gas inhalation. Here, we questioned whether CORM-3, a well-characterized water-soluble CORM, could prevent and reverse pulmonary hypertension (PH) in chronically hypoxic mice and in smooth muscle promoter 22 serotonin transporter mice overexpressing the serotonin transporter in smooth muscle cells (SMCs).

APPROACH AND RESULTS:

Treatment with CORM-3 (50 mg/kg per day once daily) for 3 weeks prevented PH, right ventricular hypertrophy, and distal pulmonary artery muscularization in mice exposed to chronic hypoxia and partially reversed PH in smooth muscle promoter 22 serotonin transporter mice by reducing Ki67 dividing pulmonary artery SMCs (PA-SMCs). In these models, CORM-3 markedly increased lung p21 mRNA and protein levels and p21-stained PA-SMCs. These effects contrasted with the transient pulmonary vasodilatation and rise in lung cGMP levels induced by a single injection of CORM-3 in mice exposed to acute hypoxia. Studies in cultured rat PA-SMCs revealed that the inhibitory effects of CORM-3 on cell growth were independent of cGMP formation but associated with increased p21 mRNA and protein levels. Protection against PH by CORM-3 required increased lung expression of p21, as indicated by the inability of CORM-3 to prevent chronic hypoxia-induced PH in p21-deficient mice and to alter the growth of PA-SMCs derived from p21-deficient mice. CORM-3-induced p21 overexpression was linked to p53 activation as assessed by the inability of CORM-3 to prevent PH and induce p21 expression in p53-deficient mice and in PA-SMCs derived from p53-deficient mice.

CONCLUSIONS:

CORM-3 inhibits pulmonary vascular remodeling via p21, which may represent a useful approach for treating PH.

• Authors: Shariq Abid, Amal Houssaïni, Nathalie Mouraret, Elisabeth Marcos, Valerie Amsellem, Feng Wan, Jean Luc Dubois-Randé, Geneviève Derumeaux, Jorge Boczkowski, Roberto Motterlini, Serge Adnot
• Journal: Arteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 34 Issue 2 Pg. 304-12 (Feb 2014) ISSN: 1524-4636 [Electronic] United States
• PMID: 24334871 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antihypertensive Agents
• Cdkn1a protein, mouse
• Cdkn1a protein, rat
• Cyclin-Dependent Kinase Inhibitor p21
• Microfilament Proteins
• Muscle Proteins
• Organometallic Compounds
• RNA, Messenger
• Serotonin Plasma Membrane Transport Proteins
• Slc6a4 protein, mouse
• Tumor Suppressor Protein p53
• transgelin
• tricarbonylchloro(glycinato)ruthenium(II)
• Carbon Monoxide
• Nitric Oxide Synthase Type III
• Nos3 protein, mouse
• p38 Mitogen-Activated Protein Kinases

Topics

• Animals
• Antihypertensive Agents (metabolism, pharmacology)
• Apoptosis (drug effects)
• Arterial Pressure (drug effects)
• Carbon Monoxide (metabolism)
• Cell Proliferation (drug effects)
• Cells, Cultured
• Cyclin-Dependent Kinase Inhibitor p21 (deficiency, genetics, metabolism)
• Disease Models, Animal
• Hypertension, Pulmonary (drug therapy, etiology, genetics, metabolism, pathology, physiopathology)
• Hypertrophy, Right Ventricular (etiology, metabolism, prevention & control)
• Hypoxia (complications)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Mice, Transgenic
• Microfilament Proteins (metabolism)
• Muscle Proteins (metabolism)
• Muscle, Smooth, Vascular (drug effects, metabolism, pathology, physiopathology)
• Myocytes, Smooth Muscle (drug effects, metabolism, pathology)
• Nitric Oxide Synthase Type III (metabolism)
• Organometallic Compounds (metabolism, pharmacology)
• Promoter Regions, Genetic
• Pulmonary Artery (drug effects, metabolism, pathology, physiopathology)
• RNA, Messenger (metabolism)
• Rats
• Serotonin Plasma Membrane Transport Proteins (genetics, metabolism)
• Time Factors
• Transfection
• Tumor Suppressor Protein p53 (deficiency, genetics)
• p38 Mitogen-Activated Protein Kinases (metabolism)