FTZ Ameliorates Diabetic Cardiomyopathy by Inhibiting Inflammation and Cardiac Fibrosis in the Streptozotocin-Induced Model

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.

Role of the CCL2-CCR2 axis in cardiovascular disease: Pathogenesis and clinical implications

“…Fufang Zhenzhu Tiao Zhi (FTZ) formula is a traditional herbal remedy for the treatment of disorders of glucose and lipid metabolism ( 154 ). FTZ can reduce serum IL-12 and CCL2 levels and cardiac IL-12, IL-6 and CCR2 mRNA levels in streptozotocin-induced diabetes and improve streptozotocin induced diabetic cardiomyopathy ( 155 ). Gui Zhi Tang can reduce the levels of IL-6, CCL2, IL-1β, MMP2, and MMP9 in Dahl salt-sensitive rats, reducing the area of myocardial fibrosis and exerting antihypertensive effects ( 156 ).…”

The Role of PKC-MAPK Signalling Pathways in the Development of Hyperglycemia-Induced Cardiovascular Complications

“…These extracellular stimuli include cellular stress, adhesion molecules, and neurohormones as well as PKC [ 45 , 46 , 47 ]. Increasing evidence shows that different members of the MAPK family are critically involved in regulating signalling pathways, ultimately leading to cardiac remodelling and vascular complications [ 48 , 49 , 50 , 51 , 52 , 53 ]. These biological events result from signal transduction and regulation by the four MAPK subfamilies, which are extracellular-signal-regulated kinases (ERK1/2), c-Jun NH2-terminal kinases (JNK 1, 2 and 3), and p38 MAPK.…”

CCAAT/Enhancer-Binding Proteins in Fibrosis: Complex Roles Beyond Conventional Understanding

“…Although C/EBP β may be involved in the physiologic remolding of cardiomyocytes, the relationship between change in C/EBP β protein level or activity and cardiac fibrosis under pathological conditions remains unclear. DCM can induce severe fibrosis and inhibit C/EBP β expression in heart tissue [ 34 , 293 ], while C/EBP β overexpression can inhibit cardiac fibrosis caused by DCM [ 34 ]. In addition, enhanced cardiac fibrosis, decreased cardiac functions, and high heart C/EBP β protein levels have been observed in models of experimental autoimmune myocarditis (EAM), spontaneously hypertensive rats, and transverse aortic constriction (TAC) [ 38 , 86 , 294 ].…”