The evolving systemic biomarker milieu in obese ZSF1 rat model of human cardiometabolic syndrome: Characterization of the model and cardioprotective effect of GDF15.
Marina StolinaXin LuoDenise DwyerChun-Ya HanRhonda ChenYing ZhangYuMei XiongYinhong ChenJun YinArtem ShkumatovBrandon AsonClarence HaleMurielle M VéniantPublished in: PloS one (2020)
Cardiometabolic syndrome has become a global health issue. Heart failure is a common comorbidity of cardiometabolic syndrome. Successful drug development to prevent cardiometabolic syndrome and associated comorbidities requires preclinical models predictive of human conditions. To characterize the heart failure component of cardiometabolic syndrome, cardiometabolic, metabolic, and renal biomarkers were evaluated in lean and obese ZSF1 19- to 32-week-old male rats. Histopathological assessment of kidneys and hearts was performed. Cardiac function, exercise capacity, and left ventricular gene expression were also analyzed. Obese ZSF1 rats exhibited multiple features of human cardiometabolic syndrome by pathological changes in systemic renal, metabolic, and cardiovascular disease circulating biomarkers. Hemodynamic assessment, echocardiography, and decreased exercise capacity confirmed heart failure with preserved ejection fraction. RNA-seq results demonstrated changes in left ventricular gene expression associated with fatty acid and branched chain amino acid metabolism, cardiomyopathy, cardiac hypertrophy, and heart failure. Twelve weeks of growth differentiation factor 15 (GDF15) treatment significantly decreased body weight, food intake, blood glucose, and triglycerides and improved exercise capacity in obese ZSF1 males. Systemic cardiovascular injury markers were significantly lower in GDF15-treated obese ZSF1 rats. Obese ZSF1 male rats represent a preclinical model for human cardiometabolic syndrome with established heart failure with preserved ejection fraction. GDF15 treatment mediated dietary response and demonstrated a cardioprotective effect in obese ZSF1 rats.
Keyphrases
- heart failure
- left ventricular
- adipose tissue
- gene expression
- metabolic syndrome
- weight loss
- endothelial cells
- type diabetes
- cardiovascular disease
- case report
- obese patients
- bariatric surgery
- body weight
- global health
- computed tomography
- induced pluripotent stem cells
- randomized controlled trial
- stem cells
- dna methylation
- acute myocardial infarction
- blood pressure
- resistance training
- insulin resistance
- coronary artery disease
- percutaneous coronary intervention
- mitral valve
- postmenopausal women
- transcatheter aortic valve replacement
- combination therapy
- clinical trial
- aortic valve
- cardiovascular risk factors