Central role of cardiac fibroblasts in myocardial fibrosis of diabetic cardiomyopathy

Figures

• 

  Figure 1. Cell types involved in myocardial fibrosis and remodeling in DCM. Transdifferentiation from cardiac fibroblast to myofibroblast is the core cellular event in cardiac fibrosis in DCM. 1) Myofibroblasts produce high level of collagen and other extracellular matrix proteins (ECM), and secrete matrix metalloproteinases (MMPs) as well as their inhibitors, tissue inhibitors of metalloproteinases (TIMPs), taking part in the progression to fibrotic remodeling. 2) Insulin resistance leads to the metabolic transformation of cardiomyocytes from glucose metabolism to fatty acid β oxidation, increased cell metabolic pressure, reactive oxygen species (ROS) and endoplasmic reticulum stress (ERS) and finally led to the death of cardiomyocytes. DAMPs released in inflammatory reaction by dead myocardial cells activate cardiac fibroblasts. 3) Immunocytes, including mast cell, Th1 cell and Mo/Mf could directly differentiate into myofibroblasts or indirectly promote cardiac fibroblast transdifferentiate into myofibroblast. 4) Endothelial cells were transformed into mesenchymal cells (EndMT), and further into myofibroblasts. In addition, fibrogenic mediators produced by endothelial cells participate…

• 

  Figure 2. The origin and physiological function of cardiac fibroblasts. Cardiomyocytes account for about 75% of the volume of myocardium, and fibroblasts accounted for about 13%. Cardiac fibroblasts including resident cardiac fibroblast and transformed cardiac fibroblast. Approximately 85% of cardiac fibroblasts come from epicardial cells, while the other 15% are derived from endothelial cells. Both of them could serve to maintain the structural integrity of the ECM network and regulate collagen renewal. By Figdraw. ECM, extracellular matrix.

• 

  Figure 3. High glucose, abnormal lipid metabolism and advanced glycation end products (AGES) affects cardiac fibroblasts in the development of diabetic cardiomyopathy. Continuous hyperglycemia stimulation up-regulates the expression of calcium-sensitive receptor (CaSR), transforming growth factor-beta1 (TGF-β), DNA methyltransferase 1 (DNMT1) and Methyl CpG binding protein 2 (MeCP2) in cardiac fibroblast, and result in the increase of collagen secretion, deposition or proliferation, eventually promote the development of DCM. Resistin released by adipocytes increased expression of profibrotic factors. Accumulation of AGES bind to its receptor, RAGE, triggering the activation of various signal cascades, leading to downstream events, such as increased oxidative stress, extracellular matrix (ECM) remodeling and myofibroblast differentiation. By Figdraw. CaSR, calcium-sensitive receptor; TGF-β, transforming growth factor-beta; SOCS3, suppression of cytokine signaling 3; p-Stat3, phosphorylation of signal transducer and activator of transcription 3; RASSF1A, ras association domain family 1 isoform A; p-ERK1/2, phosphorylation of extracellular signal-regulated kinase 1/2; HFD, high-fat diet;…

• 

  Figure 4. Mechanism of myocardial fibroblasts on myocardial fibrosis in diabetic cardiomyopathy. High glucose increases the expression and activity of TGF-β and causes a series of changes in signal pathways regulating the phenotypic transformation and synthesis function of CFs. The expressions of Interleukin (IL), including IL-6, IL-17, IL-1β and IL-33, were all up-regulated in myocardial fibroblasts attacked by HG, especially, IL-6 seems to up-regulate collagen gene by inducing transforming growth factor-beta 1 (TGF-β). At the same time, increased Ca2+ concentration regulated by CaSR could modulate the ubiquitination of Smad7 to affect DCM. By Figdraw. Smurf2, Smad specific E3 ubiquitin protein ligase 2; SnoN, SKI like proto-oncogene; Smad2/3, Smad family member 2 and Smad family member 3; Smad4, Smad family member 4; Smad7, Smad family member 7; ITCH, itchy E3 ubiquitin protein ligase; p-ERK1/2, phosphorylation of extracellular signal-regulated kinase 1/2; p-Smad3, phosphorylation of smad family member 3; p-AKT, phosphorylation of protein kinase B; p-FoxO1, phosphorylation of forkhead box O1; RhoA, ras homolog family member A; ROCK, Rho-associated coiled-coil containing kinases; SRF,…