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Pioglitazone attenuates valvular calcification induced by hypercholesterolemia
Journal article   Open access   Peer reviewed

Pioglitazone attenuates valvular calcification induced by hypercholesterolemia

Yi Chu, Donald D Lund, Robert M Weiss, Robert M Brooks, Hardik Doshi, Georges P Hajj, Curt D Sigmund and Donald D Heistad
Arteriosclerosis, thrombosis, and vascular biology, Vol.33(3), pp.523-532
03/2013
DOI: 10.1161/ATVBAHA.112.300794
PMCID: PMC3573264
PMID: 23288158
url
https://doi.org/10.1161/ATVBAHA.112.300794View
Published (Version of record) Open Access

Abstract

Development of calcific aortic valve stenosis involves multiple signaling pathways, which may be modulated by peroxisome proliferator-activated receptor-γ). This study tested the hypothesis that pioglitazone (Pio), a ligand for peroxisome proliferator-activated receptor-γ, inhibits calcification of the aortic valve in hypercholesteremic mice. Low density lipoprotein receptor(-/-)/apolipoprotein B(100/100) mice were fed a Western-type diet with or without Pio (20 mg/kg per day) for 6 months. Pio attenuated lipid deposition and calcification in the aortic valve, but not aorta. In the aortic valve, Pio reduced levels of active caspase-3 and terminal deoxynucleotidyl transferase dUTP nick end labeling staining. Valve function (echocardiography) was significantly improved by Pio. To determine whether changes in gene expression are associated with differential effects of Pio on aortic valves versus aorta, Reversa mice were fed Western diet with or without Pio for 2 months. Several procalcific genes were increased by Western diet, and the increase was attenuated by Pio, in aortic valve, but not aorta. Pio attenuates lipid deposition, calcification, and apoptosis in aortic valves of hypercholesterolemic mice, improves aortic valve function, and exhibits preferential effects on aortic valves versus aorta. We suggest that Pio protects against calcific aortic valve stenosis, and Pio or other peroxisome proliferator-activated receptor-γ ligands may be useful for early intervention to prevent or slow stenosis of aortic valves.
 Calcinosis - genetics Calcinosis - diagnosis Aortic Valve Stenosis - genetics Apoptosis - drug effects Cholesterol - blood Aortic Valve - drug effects Caspase 3 - metabolism Aorta - metabolism PPAR gamma - metabolism Hypercholesterolemia - drug therapy Aortic Valve - pathology Aortic Valve Stenosis - prevention & control Time Factors Receptors, LDL - deficiency Ultrasonography Female Calcinosis - metabolism Thiazolidinediones - pharmacology Osteogenesis - genetics Disease Models, Animal In Situ Nick-End Labeling Receptors, LDL - genetics Serum Amyloid A Protein - metabolism Aortic Valve - diagnostic imaging Aorta - drug effects Osteogenesis - drug effects Aortic Valve Stenosis - physiopathology Gene Expression Regulation Aortic Valve - physiopathology Apolipoprotein B-100 - deficiency Aortic Valve Stenosis - diagnosis Biomarkers - blood Apolipoprotein B-100 - genetics Aortic Valve - metabolism Mice, Knockout Adiponectin - blood Animals Hypercholesterolemia - diagnosis PPAR gamma - agonists Aortic Valve Stenosis - metabolism Calcinosis - prevention & control Mice Enzyme Activation Hypercholesterolemia - genetics Blood Glucose - metabolism Hypercholesterolemia - metabolism Calcinosis - physiopathology

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