Development of a Mouse Model of Metabolic Syndrome, Pulmonary Hypertension, and Heart Failure with Preserved Ejection Fraction
| Autor: | Marta Bueno, Elena A. Goncharova, Jeffrey J. Baust, Dmitry A. Goncharov, Mark T. Gladwin, Timothy N. Bachman, Rebecca Vanderpool, Yen-Chun Lai, Ana L. Mora, Josiah E. Radder, Neil J. Kelly, Jian Hu, Steven D. Shapiro, Alison Morris, Qingqing Meng |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Respiratory System Clinical Biochemistry Blood Pressure Cardiorespiratory Medicine and Haematology 030204 cardiovascular system & hematology Cardiovascular Mice 0302 clinical medicine pulmonary hypertension-heart failure with preserved ejection fraction Diastole pulmonary hypertension 2.1 Biological and endogenous factors Medicine Aetiology Original Research AKR/J Metabolic Syndrome pulmonary hypertension–heart failure with preserved ejection fraction Pulmonary Heart Disease Hypertension Disease Progression Cardiology Inbred AKR Pulmonary and Respiratory Medicine medicine.medical_specialty Systole Hypertension Pulmonary Diet High-Fat metabolic syndrome Mice Inbred AKR 03 medical and health sciences Insulin resistance Internal medicine Animals Obesity Molecular Biology Nutrition Heart Failure Animal business.industry Prevention Reproducibility of Results Stroke Volume Cell Biology medicine.disease Pulmonary hypertension Diet Disease Models Animal High-Fat 030104 developmental biology Blood pressure Endocrinology Heart failure Disease Models group 2 pulmonary hypertension Metabolic syndrome Heart failure with preserved ejection fraction business |
| Zdroj: | American journal of respiratory cell and molecular biology, vol 56, iss 4 |
| ISSN: | 1535-4989 1044-1549 |
| DOI: | 10.1165/rcmb.2016-0177oc |
| Popis: | Pulmonary hypertension (PH) associated with heart failure with preserved ejection fraction (PH-HFpEF; World Health Organization Group II) secondary to left ventricular (LV) diastolic dysfunction is the most frequent cause of PH. It is an increasingly recognized clinical complication of the metabolic syndrome. To date, no effective treatment has been identified, and no genetically modifiable mouse model is available for advancing our understanding for PH-HFpEF. To develop a mouse model of PH-HFpEF, we exposed 36 mouse strains to 20 weeks of high-fat diet (HFD), followed by systematic evaluation of right ventricular (RV) and LV pressure-volume analysis. The HFD induces obesity, glucose intolerance, insulin resistance, hyperlipidemia, as well as PH, in susceptible strains. We observed that certain mouse strains, such as AKR/J, NON/shiLtJ, and WSB/EiJ, developed hemodynamic signs of PH-HFpEF. Of the strains that develop PH-HFpEF, we selected AKR/J for further model validation, as it is known to be prone to HFD-induced metabolic syndrome and had low variability in hemodynamics. HFD-treated AKR/J mice demonstrate reproducibly higher RV systolic pressure compared with mice fed with regular diet, along with increased LV end-diastolic pressure, both RV and LV hypertrophy, glucose intolerance, and elevated HbA1c levels. Time course assessments showed that HFD significantly increased body weight, RV systolic pressure, LV end-diastolic pressure, biventricular hypertrophy, and HbA1c throughout the treatment period. Moreover, we also identified and validated 129S1/SvlmJ as a resistant mouse strain to HFD-induced PH-HFpEF. These studies validate an HFD/AKR/J mouse model of PH-HFpEF, which may offer a new avenue for testing potential mechanisms and treatments for this disease. |
| Databáze: | OpenAIRE |
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