Table 3:

Effects of high glucose on cardiac fibroblast phenotype and function

Source of cardiac fibroblasts	Protocol of glucose stimulation	Effects of glucose	Proposed mechanism	Ref
15–16-week old diabetic (db/db) and lean male mice	25mM (high) vs. 5mM (normal) glucose concentration for 24h	Increased production of collagen I, TIMP-2, MMP-2, TGF-β, RAGE, PAI-1 in CFs from db/db mice under both hyperglycemic and normoglycemic conditions. In contrast glucose had no significant effects on CFs from lean animals.	N/A	[139]
8–10-week old male C57BL/6J mice and 19-week old male C57BL/6J mice following 11 weeks of diabetogenic diet	25mM (high) vs. 5.5mM (normal) glucose concentration for 72h	Increased collagen I and αSMA expressions and unchanged production of hyaluronan in CFs from mice fed diabetogenic diet under high glucose. No effects of high glucose on CFs from lean mice in terms of proliferation, hyaluronan or collagen I production and αSMA expression	N/A	[85]
Adult male wistar rats	33mM (high) vs. 5mM (normal) glucose concentration for 6–24h	Increased synthesis of fibronectin	Reduction in PPARδ	[383]
1- to 3-day old Wistar rats	25mM (high) vs. 5mM (normal) glucose concentration for 4–72h	Increased synthesis of collagen I and III	Activation of extracellular signal regulated kinase (ERK) 1/2	[82]
3- to 40-day old Sprague Dawley rats	25mM (high) vs. 5mM (normal) glucose concentration for 48h	Decreased proliferation and migration of CFs, increased collagen gel remodeling and contraction, enhanced collagen synthesis and α1β1 integrin expression. No changes in α-SMA expression	N/A	[250]
1- to 3-day old Sprague-Dawley rats	30mM (high) vs. 5mM (normal) glucose concentration for 48h	Apoptosis of CFs, increased synthesis of collagen I and III	Increased oxidative stress due to decreased acetaldehyde dehydrogenase 2 (ALDH2)	[270]
0- to 2-day old Sprague-Dawley rats	High glucose (12.5mM, 17mM, 25mM) vs. 5.5mM (normal) glucose concentration for 24h, 48h or 72h	Significantly increased production of collagen 1 and TGF-β under high glucose (25mM) for 24h	Activation of intracellular RAS	[88]
1- to 3-day old Wistar rats	40mM (high) vs. 5.5mM (normal) glucose concentration for 48h	Increased proliferation, upregulated α-SMA, collagen-I/-III, and MMP-2/-9 protein expression	Endoplasmic reticulum stress and activation of Wnt/β-catenin	[465]
1- to 3-day old Wistar rats	40mM (high) vs. 5.5mM (normal) glucose concentration for 24h	Increased viability, migration, proliferation and production of collagen I/III and MMP-2, -9	Activation of calcium-sensitive receptor (CaSR)/intracellular Ca2+/TGF-β1/Smads pathway	[258]
Neonatal Sprague-Dawley rats	33.3mM (high) vs. 5.5mM (normal) glucose concentration for 24h	Increased proliferation, α-SMA and collagen-I expressions	Activation of Methyl CpG binding protein 2 (MeCP2)/Ras association domain family 1 isoform A (RASSF1A)/Ras/ERK1/2 pathway	[466]
neonatal Sprague–Dawley rats	30mM (high) vs. 5.5mM (normal) glucose concentration for 48h	Increased proliferation and production of collagen I	Increased transient receptor potential vanilloid (TRPV4) channel responsible for regulation of Ca2+ influx to CFs with consecutive activation of TGF-β1/Smad3 pathway	[87]
1-day old Sprague–Dawley rats	25mM (high) vs. 5.6mM (normal) glucose concentration for 24h	Increased proliferation, collagen synthesis	Activation of TGF-β1/pSmad2/3 pathway through increased oxidative stress	[467]
Neonatal C57BL/6 mice	30mM (high) vs. 5.5mM (normal) glucose concentration for 24h	Enhanced collagen I and collagen III expressions	Activation of Kcnq1ot1/miR-214-3p/NLRP3 inflammasome/caspase-1/Il-1β/TGF-β1/Smad pathway	[326]
Right atrium of patients with arterial hypertension and dyslipidemia undergoing cardiac surgery	15mM and 25mM (high) vs. 5.0mM (normal) glucose concentration for 24h, 48h and 72h	Increased proliferation	N/A	[468]
Human cardiac fibroblasts	25mM (high) vs. 5.0mM (normal) glucose concentration for 48h	Increase in proliferation and apoptosis, acquisition of α-SMA, increase in expression of collagens I and III, and TGF-β1 Bigger changes in higher glucose	miR-32-5p-dependent decrease in expression of dual specificity phosphatase 1 (DUSP1)	[469]
Primary human cardiac fibroblast cells (ACBRI 5118)	25mM and 100mM (high) vs. 5.5mM (normal) glucose concentration for 1, 2, 4, 6, 12, 24, and 48 h	Upregulation of MMP-2 and TIMP-1	Upregulation of SGLT1	[470]
Primary human cardiac fibroblast cells	25mM (high) vs. 5.5mM (normal) glucose concentration for 24h	Increased cell viability and proliferation, elevated α-SMA expression, production of collagens I, III and VI	Downregulation of miR-9 and upregulation of TGFβRII	[471]