RESUMEN
Based on the correlation between Qi and blood in traditional Chinese medicine， the collateral disease theory puts forward that the Qi-collateral go hand in hand with the vessel-collateral of the brain， and to be as close as lips to teeth in structure and function， which is an important basis for the function of brain governing mind. And this theory proposes that deficiency/stagnancy of collateral-Qi， stagnation of collaterals and loss of consciousness are the main pathogenesis of Alzheimer's disease（AD）， which is different from the research strategy of modern medicine focusing on neurons. It is suggested that it is necessary to treat AD from two aspects， including neuronal protection（elimination of pathological products such as β-amyloid and phosphorylated tau protein） and cerebral microvascular protection（protection of cerebral microvascular structure and function， promotion of therapeutic angiogenesis and increase of cerebral blood flow. Tongxinluo capsules is a representative drug for dredging collaterals developed under the guidance of the therapeutic principle of collaterals need circulation， it can protect microvessels and play a neuroprotective role mediated by vascular protection. Clinical studies have confirmed that Tongxinluo capsules can effectively treat AD， vascular dementia and cognitive impairment related diseases， which can provide new ideas and effective treatment ways to prevent and treat AD from neurovascular protection in a comprehensive manner.
RESUMEN
<p><b>Background</b>Our previous studies have shown that Tongxinluo (TXL), a compound Chinese medicine, can decrease myocardial ischemia-reperfusion injury, protect capillary endothelium function, and lessen cardiac ventricle reconstitution in animal models. The aim of this study was to illuminate whether TXL can improve hypercholesterolemia-impaired heart function by protecting artery endothelial function and increasing microvascular density (MVD) in heart. Furthermore, we will explore the underlying molecular mechanism of TXL cardiovascular protection.</p><p><b>Methods</b>After intragastric administration of TXL (0.1 ml/10 g body weight) to C57BL/6J wild-type mice (n = 8) and ApoE-/- mice (n = 8), total cholesterol, high-density lipoprotein-cholesterol, very-low-density lipoprotein (VLDL)-cholesterol, triglyceride, and blood glucose levels in serum were measured. The parameters of heart rate (HR), left ventricular diastolic end diameter, and left ventricular systolic end diameter were harvested by ultrasonic cardiogram. The left ventricular ejection fraction, stroke volume, cardiac output, and left ventricular fractional shortening were calculated. Meanwhile, aorta peak systolic flow velocity (PSV), end diastolic flow velocity, and mean flow velocity (MFV) were measured. The pulsatility index (PI) and resistant index were calculated in order to evaluate the vascular elasticity and resistance. The endothelium-dependent vasodilatation was evaluated by relaxation of aortic rings in response to acetylcholine. Western blotting and real-time quantitative reverse transcription polymerase chain reaction were performed for protein and gene analyses of vascular endothelial growth factor (VEGF). Immunohistochemical detection was performed for myocardial CD34 expression. Data in this study were compared by one-way analysis of variance between groups. A value of P < 0.05 was considered statistically significant.</p><p><b>Results</b>Although there was no significant decrease of cholesterol level (F = 2.300, P = 0.240), TXL inhibited the level of triglyceride and VLDL (F = 9.209, P = 0.024 and F = 9.786, P = 0.020, respectively) in ApoE-/- mice. TXL improved heart function of ApoE-/- mice owing to the elevations of LVEF, SV, CO, and LVFS (all P < 0.05). TXL enhanced aortic PSV and MFV (F = 10.774, P = 0.024 and F = 11.354, P = 0.020, respectively) and reduced PI of ApoE-/- mice (1.41 ± 0.17 vs. 1.60 ± 0.17; P = 0.037). After incubation with 10 μmol/L acetylcholine, the ApoE-/- mice treated with TXL aortic segment relaxed by 44% ± 3%, significantly higher than control group mice (F = 9.280, P = 0.040). TXL also restrain the angiogenesis of ApoE-/- mice aorta (F = 21.223, P = 0.010). Compared with C57BL/6J mice, the MVD was decreased in heart tissue of untreated ApoE-/- mice (54.0 ± 3.0/mmvs. 75.0 ± 2.0/mm; F = 16.054, P = 0.010). However, TXL could significantly enhance MVD (65.0 ± 5.0/mmvs. 54.0 ± 3.0/mm; F = 11.929, P = 0.020) in treated ApoE-/- mice. In addition, TXL obviously increased the expression of VEGF protein determined by Western blot (F = 20.247, P = 0.004).</p><p><b>Conclusions</b>TXL obviously improves the ApoE-/- mouse heart function from different pathways, including reduces blood fat to lessen atherosclerosis; enhances aortic impulsivity, blood supply capacity, and vessel elasticity; improves endothelium-dependent vasodilatation; restraines angiogenesis of aorta-contained plaque; and enhances MVD of heart. The molecular mechanism of MVD enhancement maybe relate with increased VEGF expression.</p>