Does Cell-Type-Specific Silencing of Monoamine Oxidase B Interfere with the Development of Right Ventricle (RV) Hypertrophy or Right Ventricle Failure in Pulmonary Hypertension?

Publisher: MDPI Country of Publication: Switzerland NLM ID: 101092791 Publication Model: Electronic Cited Medium: Internet ISSN: 1422-0067 (Electronic) Linking ISSN: 14220067 NLM ISO Abbreviation: Int J Mol Sci Subsets: MEDLINE

Original Publication: Basel, Switzerland : MDPI, [2000-

Hypertension, Pulmonary*/genetics ; Hypertension, Pulmonary*/etiology ; Hypertension, Pulmonary*/metabolism ; Hypertension, Pulmonary*/pathology ; Hypertrophy, Right Ventricular*/metabolism ; Hypertrophy, Right Ventricular*/genetics ; Hypertrophy, Right Ventricular*/etiology ; Hypertrophy, Right Ventricular*/pathology ; Monoamine Oxidase*/genetics ; Monoamine Oxidase*/metabolism ; Monoamine Oxidase*/deficiency ; Reactive Oxygen Species*/metabolism; Animals ; Male ; Mice ; Disease Models, Animal ; Heart Failure/metabolism ; Heart Failure/etiology ; Heart Failure/genetics ; Heart Failure/pathology ; Heart Ventricles/pathology ; Heart Ventricles/metabolism ; Mice, Knockout ; Myocytes, Cardiac/metabolism ; Myocytes, Cardiac/pathology ; Ventricular Dysfunction, Right/metabolism ; Ventricular Dysfunction, Right/genetics ; Ventricular Dysfunction, Right/etiology ; Ventricular Dysfunction, Right/pathology

Increased mitochondrial reactive oxygen species (ROS) formation is important for the development of right ventricular (RV) hypertrophy (RVH) and failure (RVF) during pulmonary hypertension (PH). ROS molecules are produced in different compartments within the cell, with mitochondria known to produce the strongest ROS signal. Among ROS-forming mitochondrial proteins, outer-mitochondrial-membrane-located monoamine oxidases (MAOs, type A or B) are capable of degrading neurotransmitters, thereby producing large amounts of ROS. In mice, MAO-B is the dominant isoform, which is present in almost all cell types within the heart. We analyzed the effect of an inducible cardiomyocyte-specific knockout of MAO-B (cmMAO-B KO) for the development of RVH and RVF in mice. Right ventricular hypertrophy was induced by pulmonary artery banding (PAB). RV dimensions and function were measured through echocardiography. ROS production (dihydroethidium staining), protein kinase activity (PamStation device), and systemic hemodynamics (in vivo catheterization) were assessed. A significant decrease in ROS formation was measured in cmMAO-B KO mice during PAB compared to Cre-negative littermates, which was associated with reduced activity of protein kinases involved in hypertrophic growth. In contrast to littermates in which the RV was dilated and hypertrophied following PAB, RV dimensions were unaffected in response to PAB in cmMAO-B KO mice, and no decline in RV systolic function otherwise seen in littermates during PAB was measured in cmMAO-B KO mice. In conclusion, cmMAO-B KO mice are protected against RV dilatation, hypertrophy, and dysfunction following RV pressure overload compared to littermates. These results support the hypothesis that cmMAO-B is a key player in causing RV hypertrophy and failure during PH.

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Keywords: monoamine oxidase; pulmonary hypertension; right heart

EC 1.4.3.4 (Monoamine Oxidase)
0 (Reactive Oxygen Species)

Date Created: 20240619 Date Completed: 20240619 Latest Revision: 20240717

20240717

PMC11172614

10.3390/ijms25116212

38892401