Salvianolic acid B improves myocardial function in diabetic cardiomyopathy by suppressing IGFBP3

https://doi.org/10.1016/j.yjmcc.2020.01.009Get rights and content

Highlights

  • Sal B attenuates hyperglycemia-induced cardiac dysfunction and myocardial fibrosis by enhancing myocardial angiogenesis.

  • Sal B enhances myocardial angiogenesis by downregulation insulin-like growth factor-binding protein 3 (IGFBP3) activity.

  • Sal B downregulates IGFBP3 activity through increasing promoter DNA methylation of IGFBP3 and cytoplasmic translocation.

Abstract

Background

Salvianolic acid B (Sal B) is the representative component of phenolic acids derived from the dried root and rhizome of Salvia miltiorrhiza Bge. (Labiatae), which has been widely used for the treatment of cardiovascular and cerebrovascular diseases. However, the effect of Sal B on diabetic cardiomyopathy (DCM) is still unclear.

Methods

Type 1 diabetes mellitus was induced in C57BL/6 J mice by streptozotocin (STZ) treatment, whereas meanwhile Salvianolic Acid B (Sal B (15 or 30 mg/kg/d) was intraperitoneally injected for 16 weeks. At the end of this period, cardiac function was assessed by echocardiography, and total collagen deposition was evaluated by Masson's trichrome and Picrosirius Red staining. Human umbilical vein endothelial cells exposed to hypoxia were used to investigate the effect of different doses of Sal B on angiogenesis and tube formation in vitro. Transcriptome sequencing was performed to identify potential targets of Sal B.

Results

Sal B ameliorated left ventricular dysfunction and remodeling, and decreased collagen deposition in the heart of diabetic mice. Administration of Sal B increased the expression of vascular endothelial growth factor (VEGF) receptor 2 (VEGFR2) and VEGFA in a dose-dependent manner and promoted angiogenesis both in vivo and in vitro. Furthermore, Sal B reduced HG-induced insulin-like growth factor-binding protein 3 (IGFBP3) expression, induced the phosphorylation of extracellular signal-regulated protein kinase and protein kinase B (AKT) activities, enhanced cell proliferation, and activated VEGFR2/VEGFA signaling in endothelial cells. The underlying mechanisms involve SalB that enhances IGFBP3 promoter DNA methylation and induce nuclear translocation of IGFBP3 in HUVECs under hypoxia.

Conclusions

Sal B promoted angiogenesis and alleviated cardiac fibrosis and cardiac remodeling in DCM by suppressing IGFBP3.

Introduction

Diabetes mellitus (DM) is a major public health problem of the 21st century and the fifth leading cause of death worldwide. China has the largest number of DM patients in the world [1]. DM and its complications have become one of the major threats to modern society. Among these complications, diabetic cardiomyopathy (DCM) has been receiving extensive attention due to the associated mortality and morbidity rates. However, one cannot prevent the development of DCM by simply controlling blood glucose levels [2]. Therefore, it is important, from both the research and clinical point of view, to clarify the molecular mechanism underlying this disease and to develop effective drugs that can relieve DCM.

DCM is defined as structural and functional myocardial impairment in diabetic patients without known hypertension or coronary artery disease [3]. Lately, research on the development mechanism of DCM has been focused on the contribution of different processes, such as inflammation, lipotoxicity, glucotoxicity, endothelial-to-mesenchymal transition, cardiomyocyte apoptosis, and oxidative stress injury [[4], [5], [6], [7]], but the regulatory mechanism of angiogenesis in DCM is still poorly characterized. Studies have shown that coronary microcirculation disorders can aggravate cardiac fibrosis in diabetic patients [8]. A report has demonstrated that the expression of VEGF and its receptors VEGFR1 and VEGFR2 is decreased in the myocardial tissue of diabetic rats [9]. Another study showed that the expression of VEGF and angiopoietin-1 declined in both diabetic rats and diabetes-induced human coronary artery smooth muscle cells [10]. These studies reveal the significant role of microcirculation disorders in accelerating DCM.

Sal B is one of the main active components of Salvia miltiorrhiza, one of the favorite traditional Chinese medicines for the treatment of cardio-cerebral vascular diseases [11]. Studies have shown that Sal B could relieve ischemic cardio-cerebral vascular diseases, such as acute myocardial infarction and acute stroke, via promoting angiogenesis to ameliorate microcirculation [12,13]. However, it is unclear whether Sal B can boost angiogenesis in DCM.

In the present study, we have investigated the effect of Sal B on DCM. The results show that Sal B can alleviate cardiac fibrosis and remodel DCM by promoting angiogenesis.

Section snippets

Sal B attenuates hyperglycemia-induced myocardial remodeling

Compared with citrate-treated mice, streptozotocin (STZ)-induced diabetic mice showed significantly higher random blood glucose (RBG) and it peak at four weeks of induction. Sal B treatment had no effect on blood glucose levels (Supplemental Fig. 1). To ascertain whether Sal B plays a role in myocardial remodeling associated with diabetes, we subjected diabetic mice to control and Sal B treatment. Body weight, heart weight, and the ratio of heart weight to body weight were comparable among the

Discussion

In this study, we investigated the effects of Sal B on DCM. Our results suggested that a low dose of Sal B could improve the myocardial function of diabetic mice with DCM by attenuating hyperglycemia-induced myocardial remodeling and myocardial fibrosis. Importantly, we unveiled the molecular mechanism underlying Sal B-promoted myocardial angiogenesis, which involves the suppression of IGFBP3 activity.

Sal B, an active compound extracted from S. miltiorrhiza, has been widely and successfully

Animal model and experimental protocol

Eight-week-old C57BL/6 J male mice were purchased from Vital River Laboratory Animal Technology Co. Ltd. (Beijing, China), housed at a constant temperature (24 °C), and given a normal diet with free access to water. Mice were injected intraperitoneally with STZ (60 mg/kg body weight; Sigma-Aldrich, St. Louis, MO, USA) daily for five consecutive days. Control mice (n = 20) were injected with citrate buffer alone. Blood glucose was measured using an Accu-Check Active glucometer (Roche, Shanghai,

Declaration of Competing Interest

The authors declare no conflict of interest.

The following are the supplementary data related to this article.

. Glucose level in mice from all groups.

. Sal B promotes cell viability and angiogenesis in HUVECs.

A. Cell viability was measured by CCK-8 assay. B. Western blot analysis of VEGFR2 and VEGFA expression at 12 and 24 h of treatment.

Acknowledgements

The study was supported by the National Natural Science Foundation of China (No. 81970251, 81100206, 91839301).

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