Increased Calcific Aortic Valve Disease in response to a diabetogenic, procalcific diet in the LDLr -/- ApoB 100/100 mouse model

Autor: Marta Scatena, Elizabeth M. Leaf, Cecilia M. Giachelli, Melissa F. Jackson, Mary C. Wallingford, Mei Y. Speer
Rok vydání: 2018
Předmět:
Blood Glucose
Male
0301 basic medicine
Aortic valve
Time Factors
Apolipoprotein B
030204 cardiovascular system & hematology
Ventricular Function
Left
0302 clinical medicine
Hyperlipidemia
Cells
Cultured
Mice
Knockout
Ejection fraction
biology
Calcinosis
General Medicine
Lipids
Phenotype
medicine.anatomical_structure
Aortic Valve
Apolipoprotein B-100
lipids (amino acids
peptides
and proteins)
Cardiology and Cardiovascular Medicine
Cardiac function curve
medicine.medical_specialty
Hyperlipidemias
Article
Pathology and Forensic Medicine
03 medical and health sciences
Internal medicine
medicine
Animals
Genetic Predisposition to Disease
Apolipoproteins B
business.industry
Hemodynamics
nutritional and metabolic diseases
Stroke Volume
Aortic Valve Stenosis
medicine.disease
Diet
Disease Models
Animal
030104 developmental biology
Endocrinology
Diabetes Mellitus
Type 2
Receptors
LDL
LDL receptor
biology.protein
Metabolic syndrome
business
Papio
Calcification
Zdroj: Cardiovascular Pathology. 34:28-37
ISSN: 1054-8807
DOI: 10.1016/j.carpath.2018.02.002
Popis: Objective Calcific aortic valve disease (CAVD) is a major cause of aortic stenosis (AS) and cardiac insufficiency. Patients with type II diabetes mellitus (T2DM) are at heightened risk for CAVD, and their valves have greater calcification than nondiabetic valves. No drugs to prevent or treat CAVD exist, and animal models that might help identify therapeutic targets are sorely lacking. To develop an animal model mimicking the structural and functional features of CAVD in people with T2DM, we tested a diabetogenic, procalcific diet and its effect on the incidence and severity of CAVD and AS in the, LDLr -/- ApoB 100/100 mouse model. Results LDLr -/- ApoB 100/100 mice fed a customized diabetogenic, procalcific diet (DB diet) developed hyperglycemia, hyperlipidemia, increased atherosclerosis, and obesity when compared with normal chow fed LDLr -/- ApoB 100/100 mice, indicating the development of T2DM and metabolic syndrome. Transthoracic echocardiography revealed that LDLr -/- ApoB 100/100 mice fed the DB diet had 77% incidence of hemodynamically significant AS, and developed thickened aortic valve leaflets and calcification in both valve leaflets and hinge regions. In comparison, normal chow (NC) fed LDLr -/- ApoB 100/100 mice had 38% incidence of AS, thinner valve leaflets and very little valve and hinge calcification. Further, the DB diet fed mice with AS showed significantly impaired cardiac function as determined by reduced ejection fraction and fractional shortening. In vitro mineralization experiments demonstrated that elevated glucose in culture medium enhanced valve interstitial cell (VIC) matrix calcium deposition. Conclusions By manipulating the diet we developed a new model of CAVD in T2DM, hyperlipidemic LDLr -/- ApoB 100/100 that shows several important functional, and structural features similar to CAVD found in people with T2DM and atherosclerosis including AS, cardiac dysfunction, and inflamed and calcified thickened valve cusps. Importantly, the high AS incidence of this diabetic model may be useful for mechanistic and translational studies aimed at development of novel treatments for CAVD.
Databáze: OpenAIRE
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