Shexiang Tongxin Dropping Pills Promote Macrophage Polarization-Induced Angiogenesis Against Coronary Microvascular Dysfunction via PI3K/Akt/mTORC1 Pathway

Abstract

Background: Accumulating evidence suggests that coronary microvascular dysfunction (CMD) is one of the important causes of coronary artery diseases. Angiogenesis can effectively improve CMD by increasing blood supply capacity, recovering cardiac function and poor hemodynamics. Clinical studies have approved Shexiang Tongxin dropping pill (STDP), which has exerted remarkable roles on ameliorating CMD, but the effects and mechanisms of STDPs on angiogenesis have not been clarified.Purpose: The purpose of this study was to elucidate the effects and potential mechanisms of STDPs on macrophage polarization-induced angiogenesis against CMD.Methods: Echocardiography, optical microangiography (OMAG), and histological examination were applied to evaluate cardioprotection and proangiogenic effects of STDPs on left anterior descending (LAD) ligation-induced CMD rats. In vitro, oxygen–glucose deprivation–reperfusion (OGD/R)-induced HUVEC model and LPS-stimulated bone marrow-derived macrophage (BMDM) model were established to observe the effects of STDPs on angiogenesis and M2 macrophage polarization.Results: STDPs improved cardiac function, increased microvascular density, and the number of M2 macrophages in the heart of CMD rats. In vitro, STDPs accelerated the proliferation, migration, and tube formation in OGD/R-induced HUVECs similar to the effects of VEGF-A. Furthermore, in LPS-stimulated BMDMs model, STDPs modulated M2 macrophage polarization and increased VEGF-A release via the PI3K/AKT/mTORC1 pathway.Conclusion: STDPs promoted macrophage polarization-induced angiogenesis against CMD via the PI3K/Akt/mTORC1 pathway. Our results demonstrated that the phenotype transformation of macrophages and stimulating the secretion of VEGF-A may be applied as novel cardioprotective targets for the treatment of CMD.

Prenatal High‐Sucrose Diet Induced Vascular Dysfunction of Renal Interlobar Arteries in the Offspring via PPARγ‐RXRg‐ROS/Akt Signaling

“…Notably, Akt kinase could mediate microvascular dysfunction by regulating endothelial nitric oxide synthase (eNOS), and also played a critical role in many important cellular processes. [28,29] The relative mRNA level of Akt in HS detected by RNA-Seq with fold of change = 1.67 (Figure 5E), similar to the mRNA and protein expressions respectively detected by real-time PCR and western blot (Figure 5F). Capivasertib, as the Akt inhibitor, significantly inhibited PE-induced vascular tension in both CON and HS groups (Figure 5G,H).…”

Chinese patent medicines for coronary microvascular disease: clinical evidence and potential mechanisms

“…Zhang et al 83 found that Shexiang Baoxin pills regulated endothelial cell function and signal transduction pathway by activating macrophages, promoting human umbilical vein endothelial cell proliferation and migration and tubule formation, angiogenesis factor mRNA and protein expression, and promoted angiogenesis. Shexiang Tongxin dropping pills clould alleviate cardiac dysfunction in rats with CMD caused by ligation of the left anterior descending branch by inducing M2 macrophage polarization to promote angiogenesis in ischemic myocardium 84 . Vascular growth factors such as VEGF and basic fibroblast growth factor (bFGF) are helpful to increase vascular permeability, angiogenesis and intravascular homeostasis.…”

Macrophage Polarization, Metabolic Reprogramming, and Inflammatory Effects in Ischemic Heart Disease

“…Although this innate anti-inflammatory effect is necessary for the defense against bacterial infection, it may still cause excessive inflammatory injury to the myocardial tissue, whereas the inflammatory stimulus promotes excessive fibroblast activation, causing excessive myocardial fibrosis and affecting the left ventricular systolic-diastolic function ( 48 , 56 ). This introduces the reparative effect of M2 macrophages during the repair phase, which, unlike M1 macrophages, promote inflammatory regression, enhance fragment phagocytosis, and promote the powerful effect of revascularization in myocardial ischemic injury ( 59 ). Activation of M2 macrophages in the heart overlaps in time with M1, typically at 4 to 14 days, produced by Ly6C low monocytes ( 60 ).…”