Study Of Mevalonate Pathway Related Enzyme On Cardiac Hypertrophy And Associated Heart Failure With Preserved Ejection Fraction Induced By Pressure Overload In Rats

Part1Building a model of cardiac hypertrophy and associated heart failure with preserved ejection fraction induced by pressure overload in ratsBackground:Heart failure with preserved ejection fraction (HFpEF) is the clinical syndrome of heart failure characterized by impaired diastolic function but normal systolic function, accounting for approximately40%of heart failure cases overall. HFpEF, which has an increasing rate of morbidity and mortality, has a poor prognosis due to the shortage of effective therapy. Common conditions causing HFpEF include, hypertension, diabetes, obesity and advanced age. Diastolic dysfunction is present in half of patients with hypertension. As the mechanism of HFpEF is still not fully understood, further study would give some good idea to exploring effective therapies.Aims:Building a model of pressure overload-induced cardiac hypertrophy and associated heart failure with preserved ejection fraction by suprarenal abdominal aortic coarctation in rats.Methods:(1) Building a model of pressure overload by suprarenal abdominal aortic coarctation (AAC) and a sham model (sham).(2) Cardiac function and hemodynamics were evaluated at3,5,8and14weeks post-operatively by echocardiography and carotid catheterization.(3) Plasma BNP was measured by Enzyme Immunoassay (EIA) kit.(4) Remodeling of left ventricle and abdominal aorta were measured.Results:(1) Blood pressure in the AAC group was elevated markedly compared with the sham group at3,5,8and14weeks post-operatively.(2) Remodeling of left ventricle and abdominal aorta proximal to the coarctation in the AAC group were significantly obvious compared with the sham group at3,5,8and14weeks post-operatively.(3) Plasma BNP in the AAC group was elevated markedly compared with the sham group at3,5,8and14weeks post-operatively.(4) Left ventricular diastolic function in the AAC group was impaired but with normal systolic function at8and14weeks post-operatively.Conclusions:Blood pressure was elevated markedly after suprarenal abdominal aortic coarctation, and remodeling of left ventricle and abdominal aorta was induced, at last, heart failure with preserved ejection fraction was induced. Part2Alteration of mevalonate pathway related enzyme expressions in pressure overload-induced cardiac hypertrophy and associated heart failure with preserved ejection fraction in ratsBackground:Heart failure with preserved ejection fraction (HFpEF) is the clinical syndrome of heart failure characterized by diastolic dysfunction, with a high rate of morbidity and mortality. Due to the shortage of effective therapy, the prognosis for patients with HFpEF remains poor. Several studies have found a survival benefit in patients with HFpEF who are receiving statin therapy, which mainly exerts a competitive inhibition on3-hydroxy-3-methylglutaryl coenzyme A reductase(HMGR) in the mevalonate pathway. Abnormalities of the mevalonate pathway, an important cellular metabolic pathway, are common in many diseases including cardiovascular disease. Diastolic dysfunction is present in half of patients with hypertension. The expression of mevalonate pathway related enzyme in pressure overload-induced cardiac hypertrophy and associated heart failure with preserved ejection fraction in rats remains unknown.Aims:To determine whether the expression of mevalonate pathway related enzyme in pressure overload-induced cardiac hypertrophy and associated heart failure with preserved ejection fraction in rats are altered and the relationship with cardiovascular remodelling.Methods:With the model of cardiac hypertrophy and associated heart failure with preserved ejection fraction induced by pressure overload in rats (Part1), we tried to explore the expression of mevalonate pathway related enzyme in left ventricle (LV), abdominal aorta and liver, such as,3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR), farnesyl diphosphate synthase (FDPS), squalene synthase (SQS), farnesyltransferase-α (FNTA), farnesyltransferase-β (FNTB), geranylgeranyltransferase type Ⅰ (GGTase-Ⅰ), extracellular signal-regulated kinase (ERK1/2), phosphorylated extracellular signal-regulated kinase (P-ERK1/2), Ras and RhoA. The activation of Ras, RhoA, Cdc42and Racl was also measured by G-LISA kit.Results:The expression of HMGR, FDPS, FNTA, FNTB and P-ERK in the LV of AAC group was elevated markedly at3,5,8and14weeks post-operatively, the expression of FDPS, FNTA and FNTB in the abdominal aorta proximal to the coarctation was elevated markedly at3,5,8and14weeks post-operatively. The expression of GGTase-I in the LV and abdominal aorta proximal to the coarctation was elevated only at14weeks post-operatively, while the expression of GGTase-I was reduced in the abdominal aorta distal to the coarctation. The expression of P-ERK1/2was elevated at both sides of the coarctation. The activation of Ras was enhanced in the LV and abdominal aorta at3,5,8and14weeks post-operatively, while the activation of RhoA was enhanced only at14weeks post-operatively.Conclusions:Cardiac hypertrophy and associated heart failure with preserved ejection fraction induced by pressure overload in rats was accompanied by altered expression of several key enzymes in the mevalonate pathway and activation of its downstream small G proteins, likely through the FDPS/FNTA、FNTB/Ras/MAPK/ERK pathway.