Hypercholesterolemia (HC) induced endothelial cell dysfunction and decreased endothelial
nitric oxide formation results in impaired angiogenesis and subsequent cardiovascular disorders. Therapeutic angiogenesis is known to be a novel strategy for treatment of patients with
ischemic heart disease. We have shown that
secoisolariciresinol diglucoside (SDG) is angiogenic as well as cardioprotective against
myocardial ischemia. In the present study, we examined the efficacy of SDG in a hypercholesterolemic
myocardial infarction (MI) model. The rats were maintained on a normal and high
cholesterol diet (2%) for 8 weeks followed by
oral administration of SDG (20 mg/kg) for 2 weeks. The rats were divided into four groups (n=24 in each): Control (C); SDG control (SDG); HC; and HC+SDG (HSDG). Isolated hearts subjected to 30 min of global
ischemia followed by 120 min of reperfusion were used to measure the cardiac functions,
infarct size and to examine the
protein expression profile.
After treatment, MI was induced by ligating the left anterior descending artery. Echocardiographic parameters were examined 30 days after MI. Significant reduction in total
cholesterol, LDL-
cholesterol,
triglycerides and an increase in
HDL-cholesterol levels were observed in HSDG as compared to the HC. Decreased
infarct size was observed in the HSDG group (43%) compared to the HC (54%). Increased phosphorylation of
endothelial nitric oxide synthase (p-eNOS) (3.1-fold),
vascular endothelial growth factor (1.9-fold) and
heme oxygenase-1 (2.3-fold) was observed in the HSDG group as compared to the HC group. Significant improvement in left ventricular functions was also observed in the HSDG group as evidenced by increased ejection fraction (55% vs. 45%), fractional shortening (28% vs. 22%) and decreased left ventricular inner diameter in systole (8 vs. 6 mm) in HSDG compared to HC. Moreover, MI model has shown increased capillary density (2531 vs. 1901) and arteriolar density (2.6 vs. 1.8) in SDG-treated rats as compared to the HC. The increased capillary and arteriolar density along with increased left ventricular functions on SDG treatment might be due to increased HO-1,
VEGF and p-eNOS expression. In conclusion, our study demonstrates for the first time that SDG treatment reduces
ventricular remodeling by neovascularization of the infarcted HC myocardium.