Table 1.
Anti-fibrotic effects of polyphenols on cardiac fibrosis.
| Study type | Class | Polyphenols | Study design | Dose | Actions | Reference |
|---|---|---|---|---|---|---|
| In vivo | Flavonols/flavan-3-ols | Quercetin | Male Wistar rats induced by ISO | 25 or 50 mg/kg | ↓TGF-β1, CTGF ↓Deposition of ECM |
Li et al., 2013 |
| Taxifolin | Male C57/BL6 mice induced by TAC | Feed containing 0.2% taxifolin | ↓TGF-β, Collagen I, Collagen III, CTGF ↓TGF-β/Smad signaling pathway |
Guo et al., 2015 | ||
| Isorhamnetin | C57/BL6 mice induced by TAC | 100 mg/kg/day for | ↓Collagen I, Collagen III, CTGF ↓PI3K–AKT signaling pathway |
Gao et al., 2017 | ||
| Troxerutin | Mus musculus fed HFFD | 150 mg/kg | ↓TGF-β, α-SMA, NOX p22phox ↓MMP-9/TIMP-1 and MMP-2/TIMP-2 ratio |
Geetha et al., 2015 | ||
| (-)-epicatechin | δ-sarcoglycan (δ-SG) null mice | 1 mg/kg | ↑SOD2, catalase, and citrate synthase ↓Cardiac fibrosis |
Ramirez-Sanchez et al., 2014 | ||
| Catechins | Lewis rats immunized with PCM | 20 mg/kg/day | ↓T cell proliferation ↓TNF-α, IL-2, cardiac fibrosis |
Suzuki et al., 2007 | ||
| Flavones/isoflavones | Luteolin | SD rats induced by Ang II | 2.3 g and 3.5 g/10 kg chow | ↓NOX2 and NOX4 ↓P-JNK and TGF-β1 |
Nakayama et al., 2015 | |
| L7DG | C57BL/6J mice induced by ISO | 40 mg/kg | ↓NOX subunits: Cyba, Cybb, Ncf1, Ncf4, Rac2 ↓Col1a1, Col1a2, Col3a1, Col12a1, Fbn1 |
Ning et al., 2017 | ||
| Baicalein/ | SHR | 50, 200 mg/kg | ↓P-ERK and MMP-9 | Kong et al., 2011 | ||
| Apigenin | Wistar rats induced by AMI | 10, 20, and 40 mg/kg | ↓TNF-α, IL-1β, IL-6 ↓MMP-9 and NF-κB |
Du et al., 2015 | ||
| Scutellarin | Wistar rats induced by LAD ligation | 10 and 30 mg/kg | ↓TGF-β1 and FN1 expression ↓P38-MAPK and ERK1/2 |
Pan et al., 2011 | ||
| Scutellarin | SD rats induced by ISO | 10, 20 mg/kg | ↓α-SMA ↑CD31, Jagged1, Notch 1, and Hes1 |
Zhou et al., 2014 | ||
| Genistein | Kunming mice induced by TAC | 50 and 100 mg/kg/day | ↓Myofibroblast transformation ↓TAK1/MKK4/JNK signaling |
Qin et al., 2015 | ||
| Anthocyanins | Cy3G | Wistar rats induced by STZ | 250mg/kg/day | ↑TIMP-1 ↓MMP-9,.TGF-β, p-MEK1/2, CTGF, P-ERK1/2, FGF2 |
Chen et al., 2016 | |
| Flavanones | Hesperetin | C57 mice subjected to AB | 30 mg/kg/day | ↓PKCα/βII/AKT and JNK activation ↓TGF-β1/Smad signaling |
Deng et al., 2013 | |
| Non-flavoniods | Resveratrol | C57/BL6 mice induced by TAC | 10 mg/kg | ↓Macrophage and mast cell infiltration ↓Oxidative stress, cardiac fibrosis |
Gupta et al., 2014 | |
| Resveratrol | SD rats subjected to AAC | 4 mg/kg | ↑SERCA2 expression ↓P-CaMKII and cardiac fibrosis |
Dong et al., 2014 | ||
| Resveratrol | C57Bl/6 mice subjected to TAC | 4 g/kg AIN-93G diet | ↓Collagen 1α1 and collage 3α1, MMP-2, TIMP-1/2/3/4, collagen deposition | Sung et al., 2015 | ||
| Resveratrol | C57Bl/6 mice induced by STZ | 5 or 25 mg/kg | ↓ROS/ERK/TGF-β/periostin pathway | Wu et al., 2016 | ||
| Resveratrol | Fischer 344 rats induced by DOX | 2.5 mg/kg | ↑SIRT-1 expression ↓TGF-β/Smad3 pathway |
Cappetta et al., 2016 | ||
| Resveratrol | Wistar rats induced by DOX | 20 mg/kg/day | ↓Caspase-3, TNF-α, MDA, and TGF-β1 ↓Collagen accumulation |
Arafa et al., 2014 | ||
| Resveratrol | DOCA-salt induced hypertensive rats | 1 mg/kg/day | ↓left ventricular collagen content | Chan et al., 2011 | ||
| Other | Curcumin | SD rats subjected to I/R | 150 mg/kg | ↓MMP-9, MMP-2, collagens synthesis ↓TGF-β/Smad pathway |
Wang et al., 2012 | |
| Curcumin | SD rats subjected to I/R | 300 mg/kg | ↓Toll-like receptor 2 and MCP-1 ↓Macrophage infiltration, cardiac fibrosis |
Kim et al., 2012 | ||
| Curcumin | C57BL/6 mice fed HFD; | 50 mg/kg | ↑Nrf-2 expression ↓NF-κB, TNF-α, IL-1β, and IL-6, cardiac fibrosis |
Zeng et al., 2015 | ||
| Curcumin | HFD fed wistar rats induced by STZ | 200 mg/kg | ↓gp91phox and p47phox ↑P-Akt, P-GSK-3β |
Yu et al., 2012 | ||
| Curcumin | SD rats induced by STZ | 300 mg/kg | ↓collagen types I and III synthesis ↓TGF-β1/Smad signaling |
Guo et al., 2017 | ||
| C66 | C57BL/6 mice induced by STZ | 5 mg/kg | ↓P-JNK expression ↓TNF-α, IL-6, collagen IV, TGF-β |
Pan et al., 2014 | ||
| C66 | C57BL/6 mice induced by STZ | 5 mg/kg every other day | ↓P-JNK, CTGF, TGF-β1 | Wang et al., 2014 | ||
| Piperine | C57BL/6 mice induced by AB | 50 mg/kg in vivo | ↓AKT/GSK3β signaling ↑PPAR-γ |
Ma Z. G. et al., 2017 | ||
| Evodiamine | C57BL/6 mice induced by ISO | 50 and 100mg/kg/day | ↓Endothelial-to-mesenchymal transition ↓TGF-β/Smad pathway |
Jiang et al., 2017 | ||
| In vitro | Flavonols/flavan-3-ols | EGCG | CFs s induced by Ang II | 12.5-200 mg/L 10 umol/L 10 umol/L | ↓CFs proliferation ↓CFs proliferation ↓CFs proliferation ↓CTGF, NF-κB signaling pathway |
Sheng et al., 2009; Cai et al., 2013; Han et al., 2013 |
| 100 μmol/L | ↓P-JNK and endoglin expression ↓CFs proliferation |
Lin et al., 2016 | ||||
| Flavones/isoflavones | Luteolin | CFs stimulated by Ang II | 6.2, 12.5, and 25 μmol/L | ↓CFs proliferation and collagen synthesis ↑NO-cGMP signal pathway |
Wang A. W. et al., 2015b | |
| Baicalein/Wogonin | CFs stimulated by Ang II | 30 μmol/L; 30 μmol/L | ↓Collagen I, III expression ↓Collagen I, III expression |
Kong et al., 2010 | ||
| Non-flavoniods | Resveratrol | CFs stimulated by AngII | 80μmol/L | ↓TGF-β1/smad3 pathway ↓CFs proliferation, myofibroblast transformation |
Chen T. et al., 2015 | |
| Other | Curcumin | CFs stimulated by Ang II | 10 and 15 μmol/L | ↓CFs proliferation and migration, MMP-2/9 ↑SIRT-1 expression |
Xiao et al., 2016 | |
| Curcumin | CFs stimulated by Ang II | 5,10, and 20 umol/L | ↓CFs proliferation ↓TGF-β1/Smad2/3 pathway |
Meng et al., 2014 | ||
| Curcumin | CFs induced by Ang II | 10 and 20 μmol/L in vitro | ↓TGF-β1, MMP-9, TIMP-1, α-SMA ↓Fibroblast proliferation |
Ma J. et al., 2017 | ||
| Curcumin | CFs induced by TGF-β1 | 5, 10, and 20 μmol/L | ↓α-SMA and Col I ↓P-Smad2 and P-P38 |
Liu et al., 2016 | ||
| Curcumin | H9C2 cells induced by PA | 20 μmol/L | ↓TGF-β | Zeng et al., 2015 | ||
| Evodiamine | CFs and HUVECs stimulated by TGF-β1 | 5, 10 μmol/L | ↓α-SMA, collagen I and III, fibronectin„ CTGF ↑CD31, CD34 expression ↓P-Smad2, P-Smad3, P-ERK1/2, P-Akt |
Wu et al., 2017a |
ISO, isoproterenol; HFD, high-fat diet; HCHF, high carbohydrate, high fat diet; TAC, thoracic aorta constriction; STZ, streptozotocin; AAC, abdominal aortic constriction; SD, Sprague-Dawley; CFs, Cardiac fibroblasts; AMI, acute myocardial infarction; NOX, NAPDH oxidase; SUMO1, small ubiquitin-related modifier 1; MI, myocardial infarction; LAD, left anterior descending coronary artery; SHR, spontaneously hypertensive rats; MMP, matrix metalloprotease-9; AB, aortic banding; COX-2, cyclooxygenase-2; ECFC, endothelial colony-forming cell; TIMP-1, tissue inhibitor of matrix metalloproteinase-1; CaMK II, Ca2+ /calmodulin-dependent protein kinase II; DOCA, deoxycorticosterone acetate; I/R, ischaemia reperfusion; NRCMs, neonatal rat cardiomyocytes; ROS, reactive oxygen species; L7DG, luteolin-7-diglucuronide; FN, fibronectin; Cy3G, cyanidin-3-glucoside; FGF, fibroblast growth factor; ECM, extracellular matrix ; HFFD, high-fat high-fructose diet ; DOX, doxorubicin; SOD, Superoxide dismutase; PCM, porcine cardiac myosin.