Abstract
BackgroundInsulin resistance has been independently related to heart failure. However, the specific mechanisms of high FFA levels in the pathophysiology of heart failure in insulin-resistant states are remain largely unclear. This study investigated whether elevated circulating free fatty acids (FFA) levels result in impaired cardiac structure and function in vivo via insulin-related signaling pathways in myocardium.MethodsMale Wistar rats were randomly divided into the intralipid group (20% intralipid plus heparin infusion) and the control group (glycerol infusion). Blood samples were collected before and after 6-, 12-, and 24-h infusions. Cardiac structure and function were measured using echocardiography. Maximum velocity of myocardial contraction (+dP/dt max) and diastole (−dP/dt max) were measured using a physiological polygraph in vivo. Heart tissues were collected for western blotting.ResultsCompared with the control group, plasma FFA, plasma glucose, and serum insulin levels increased significantly in the intralipid group. With increasing infusion time, cardiac function in the intralipid group decreased gradually compared with the control group. After a 24-h infusion, early (E’, cm/s) diastolic peak velocities and (−dP/dt max) decreased significantly. Protein expression of phosphatidylinositol 3-kinase (PI3K), the serine/threonine kinase Akt, and phosphorylated Akt in myocardium increased after a 6-h infusion and decreased significantly after a 24-h infusion in the intralipid group. Protein expression of glucose transporter type 4 (GLUT4), Adenosine 5′-monophosphate -activated protein kinase (AMPK), phosphorylated AMPK(p-AMPK), and endothelial nitric oxide synthase (eNOS) in myocardium gradually decreased in the intralipid group.ConclusionsElevated FFA levels may impair cardiac function and cardiac dysfunction might result from myocardial insulin resistance with significant changes to PI3K-Akt-GLUT4 and AMPK-eNOS signaling pathways with increasing FFA levels.
Highlights
Insulin resistance has been independently related to heart failure
left ventricular (LV) structure and function After infusing for 6, 12, or 24 h, there were no significant differences in heart structure (LVIDs, LV inner dimension-diastole (LVIDd), ISVD, Left ventricular end-diastolic posterior wall thickness (LYPWT)), FS %, and EF % in the studied groups (p > 0.05) (Table 2)
Cardiac function (E, A, E’, A’, +dP/dt max, −dP/dt max) in the intralipid group decreased gradually compared with the control group
Summary
Insulin resistance has been independently related to heart failure. the specific mechanisms of high FFA levels in the pathophysiology of heart failure in insulin-resistant states are remain largely unclear. This study investigated whether elevated circulating free fatty acids (FFA) levels result in impaired cardiac structure and function in vivo via insulin-related signaling pathways in myocardium. Hyperinsulinemia insulin-resistant states could contribute to cardiac remodeling and ventricular dysfunction through the growth-promoting activity of insulin [4]. Insulin activates phosphatidylinositol 3-kinase (PI3K) -Akt signaling and promotes glucose transporter type 4 (GLUT4) translocation to the cell surface to facilitate glucose transport [5]. Studies suggest that in insulin-resistant cardiomyopathy, reduced myocardial glucose uptake [7] and damaged LV structure and function [8] are associated with alterations in Akt activity and impaired GLUT4 translocation [9, 10]
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