Title

Porphyrin-Based SOD Mimic MnTnBu OE -2-PyP Inhibits Mechanisms of Aortic Valve Remodeling in Human and Murine Models of Aortic Valve Sclerosis

Document Type

Article

Abstract

Background Aortic valve sclerosis ( AVS c), the early asymptomatic presentation of calcific aortic valve (AV) disease, affects 25% to 30% of patients aged >65 years. In vitro and ex vivo experiments with antioxidant strategies and antagonists of osteogenic differentiation revealed that AVS c is reversible. In this study, we characterized the underlying changes in the extracellular matrix architecture and valve interstitial cell activation in AVSc and tested in vitro and in vivo the activity of a clinically approved SOD (superoxide dismutase) mimic and redox-active drug MnTnBu OE -2-PyP ( BMX -001). Methods and Results After receiving informed consent, samples from patients with AVS c, AV stenosis, and controls were collected. Uniaxial mechanical stimulation and in vitro studies on human valve interstitial cells were performed. An angiotensin II chronic infusion model was used to impose AV thickening and remodeling. We characterized extracellular matrix structures by small-angle light scattering, scanning electron microscopy, histology, and mass spectrometry. Diseased human valves showed altered collagen fiber alignment and ultrastructural changes in AVS c, accumulation of oxidized cross-linking products in AV stenosis, and reversible expression of extracellular matrix regulators ex vivo. We demonstrated that MnTnBu OE -2-PyP inhibits human valve interstitial cell activation and extracellular matrix remodeling in a murine model (C57 BL /6J) of AVS c by electron microscopy and histology. Conclusions AVS c is associated with architectural remodeling despite marginal effects on the mechanical properties in both human and mice. MnTnBu OE -2-PyP controls AV thickening in a murine model of AVS c. Because this compound has been approved recently for clinical use, this work could shift the focus for the treatment of calcific AV disease, moving from AV stenosis to an earlier presentation ( AVS c) that could be more responsive to medical therapies.

Keywords

aortic valve stenosis, extracellular matrix, reactive oxygen species, valve, valve interstitial cells

Medical Subject Headings

Aged; Animals; Aortic Valve (drug effects, pathology); Aortic Valve Stenosis (prevention & control); Calcinosis (prevention & control); Cardiovascular Agents (pharmacology); Case-Control Studies; Collagen (drug effects); Disease Models, Animal; Extracellular Matrix (drug effects); Female; Humans; Male; Metalloporphyrins (pharmacology); Mice, Inbred C57BL; Microscopy, Electron, Scanning; Middle Aged; Sclerosis (prevention & control); Superoxide Dismutase (antagonists & inhibitors); Vascular Remodeling (drug effects)

Publication Date

10-16-2018

Publication Title

Journal of the American Heart Association

E-ISSN

2047-9980

Volume

7

Issue

20

First Page

e007861

PubMed ID

30371255

Digital Object Identifier (DOI)

10.1161/JAHA.117.007861

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