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. Author manuscript; available in PMC: 2022 Jan 1.
Published in final edited form as: Cell Signal. 2020 Nov 5;77:109826. doi: 10.1016/j.cellsig.2020.109826

Table 1:

In vitro effects of Smad signaling cascades in regulation of cardiac fibroblast phenotype

Species Culture Condition Smads manipulation Role of Smad Reference
Human Collagen pads Pharmacologic Smad3 inhibition with SIS3. Smad3 mediates TGF-β1-induced α-SMA and α11 integrin expression. [104]
Rat Culture plates Pharmacologic Smad3 inhibition with SIS3. Smad3 mediates TGF-β1-induced LOX expression. [102]
Rat (neonatal) Culture plates Pharmacologic Smad3 inhibition with SIS3. Smad3 mediates TGFβ1-induced cytoprotective and antiapoptotic effects in fibroblasts exposed to simulated ischemia/reperfusion [106]
Rat (neonatal) Culture plates Pharmacologic Smad3 inhibition with SIS3. Smad3 promotes cardiac myofibroblast conversion by mediating TGF-β1-induced downregulation of FoxO3a. [98]
Mouse Culture plates Smad2/Smad3 siRNA knockdown. • Smad3 mediates baseline collagen I, collagen IV, fibronectin and TSP1 synthesis.
• Smad2 mediates baseline collagen V, fibronectin, periostin and versican.		 [109]
Mouse Collagen pads/Culture plates. Smad2/Smad3 siRNA knockdown. • Smad3, but not Smad2, mediates α2 and α5 integrin expression.
• Both Smad 2 and Smad3 stimulate α-SMA incorporation into stress fibers		 [92]
Mouse Collagen pads Fibroblasts from global Smad3 null mice Smad3 mediates TGF-β1-induced transcription of tissue transglutaminase. [103]
Mouse Culture plates Fibroblasts from global Smad3 null mice Smad3 mediates TGFβ–induced collagen III and tenascin-C synthesis. [100]
Mouse Collagen pads Fibroblasts from global Smad3 null mice Smad3 mediates TGF-β-induced TIMP1 upregulation and MMP3/MMP8 suppression, promoting a matrix-preserving phenotype. [93]
Mouse Collagen pads/Culture plates Fibroblasts from global Smad3 null mice. • Smad3 accentuates contraction of fibroblast-populated lattices.
• Smad3 mediates expression of Integrins α2, α5 and β3 in pad fibroblasts.
• Smad3 mediates α-SMA synthesis only in plated fibroblasts.		 [7]
Mouse Collagen pads/Culture plates Fibroblasts from global Smad3 null mice. • Smad3 mediates anti-proliferative and promigratory effects of TGF-β.
• Smad3 mediates contraction of fibroblast-populated lattices.
• Smad3 stimulates CTGF and extracellular matrix gene synthesis.		 [94]
Mouse Culture plates Fibroblasts from global Smad3 null mice. Smad3 mediates angiotensin II-induced upregulation of Collagen I, α-SMA, TNF-α, IL-1β, and MCP-1. [140]
Mouse Collagen pads/Culture plates Cre overexpression in fibroblasts from Smad2, Smad3 and Smad2/3 fl/fl mice to delete loxP-targeted Smads. • Smad3 (but not Smad2) mediates TGF-β1-induced fibroblast-populated pad contraction.
• Both Smad2 and Smad3 stimulate expression of extracellular matrix genes (Col1a1, Col1a2, Col3a1, Fn1, Fbln1, Tnc), matrix regulators (Loxl2, Adam12, Adam30, Sparc) and cell adhesion genes (Itga2, Itga8, Itgb3).		 [101]

Col, collagen; CTGF, connective tissue growth factor; Fbln, fibulin; Fn, fibronectin; IL, interleukin; Itg, integrin; MCP, monocyte chemoattractant protein; MMP, matrix metalloproteinase; LOX, lysyl oxidase; SMA, smooth muscle actin; TIMP, Tissue inhibitor of metalloproteinases; Tnc, tenascin; TNF, tumor necrosis factor; TGF, transforming growth factor.