Abstract
Background The pathogenesis and clinical features of diabetic cardiomyopathy (DCM) have been well studied in the past decade; however, effective approaches to prevent and treat this disease are limited. Fufang Zhenzhu Tiaozhi (FTZ) formula, a traditional Chinese prescription, is habitually used to treat dyslipidemia and diabetes. Recently, several studies have reported the therapeutic effects of FTZ on cardiovascular diseases. However, the effects of FTZ on DCM have not yet been fully elucidated. This study investigated the effects of FTZ on DCM and determined the mechanisms underlying its efficacy. Methods Diabetes was induced in mice by intraperitoneal injection of streptozotocin; the mice were randomly divided into a control group (Con), diabetes group (DCM), and diabetes-treated with FTZ (DCM + FTZ). Myocardial structural alterations, fibrosis biomarkers, and inflammation were observed. Besides, the potential targets and their related signaling pathways were analyzed using network pharmacology and further verified by Western blot. Results Diabetic mice showed significant body weight loss, hyperglycemia, and excessive collagen content in the cardiac tissue, while serum and myocardial inflammatory factors significantly increased. Nerveless, treatment with FTZ for 1 month significantly improved body weight, attenuated hyperglycemia, and alleviated diabetes-associated myocardial structure and function abnormalities. Furthermore, the serum levels of interleukin 12 (IL-12) and chemokine (C–C motif) ligand 2 (CCL2) as well as the mRNA levels of cardiac IL-12, IL-6, and C–C motif chemokine receptor 2 (Ccr2) reduced after FTZ treatment. Additionally, a total of 67 active compounds and 76 potential targets related to DCM were analyzed. Pathway and functional enrichment analyses showed that FTZ mainly regulates inflammation-related pathways, including MAPK and PI3K-AKT signaling pathways. Further investigation revealed that the activities of STAT3, AKT, and ERK were augmented in diabetic hearts but decreased in FTZ-treated cardiac tissues. Conclusion Our results suggest that FTZ exhibits therapeutic properties against DCM by ameliorating hyperglycemia-induced inflammation and fibrosis via at least partial inhibition of AKT, ERK, and STAT3 signaling pathways.
Highlights
Diabetic cardiomyopathy (DCM), characterized by adverse structural remodeling, early onset diastolic dysfunction, and late-onset systolic dysfunction, is observed in diabetic patients that occurs in the absence of coronary artery disease, hypertension, valvular and congenital heart disease, leading to heart failure and death [1, 2]
Fufang Zhenzhu Tiaozhi (FTZ) was diluted in 0.5% carboxymethyl cellulose-Na (CMC-Na) (Tianjin Zhiyuan Chemical Reagent Co., Ltd., Tianjin, China), and 3 g/kg/day FTZ was used for intragastric administration to mice every day [13, 14]. e control group (Con) group and DCM group were treated with the considerable volume of 0.5% CMC-Na via intragastric administration once a day. e preparation and quality analysis of FTZ extract were consistent with the protocol described previously [15, 22]
There was no significant difference in the serum insulin level between the DCM and the DCM + FTZ groups, an increasing trend of serum insulin was observed in the DCM + FTZ group (Figure 1(c))
Summary
Diabetic cardiomyopathy (DCM), characterized by adverse structural remodeling, early onset diastolic dysfunction, and late-onset systolic dysfunction, is observed in diabetic patients that occurs in the absence of coronary artery disease, hypertension, valvular and congenital heart disease, leading to heart failure and death [1, 2]. DCM affects approximately 12% of diabetes patients, of whom approximately 22% are over 64 years old [3, 4]. A wide variety of mechanisms have been reported to be involved in DCM, including. (1) Most mechanistic studies on DCM have been conducted in animals rather than humans [6]. (2) Conventional medications for the treatment of diabetes in clinical practice are rarely used to treat DCM because they have no beneficial effects on heart function (such as glucagon-like peptide 1 receptor (GLP-1R) agonists and dipeptidyl peptidase-4 (DDP-4) inhibitors) or their potential to cause harmful cardiac involvement (such as metformin, which can cause lactic acidosis and aggravate heart damage, and thiazolidinediones, which can cause edema and heart failure (HF)) [8]. The pathogenesis of DCM has been extensively studied, efficient therapies are not available. ere are several possible reasons for this. (1) Most mechanistic studies on DCM have been conducted in animals rather than humans [6]. ese mechanisms in animal models may not be the same in humans. (2) Conventional medications for the treatment of diabetes in clinical practice are rarely used to treat DCM because they have no beneficial effects on heart function (such as glucagon-like peptide 1 receptor (GLP-1R) agonists and dipeptidyl peptidase-4 (DDP-4) inhibitors) or their potential to cause harmful cardiac involvement (such as metformin, which can cause lactic acidosis and aggravate heart damage, and thiazolidinediones, which can cause edema and heart failure (HF)) [8]. us, the clinical verification of traditional drugs and the secondary development of existing drugs are important in the prevention and treatment of DCM
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