Histone deacetyltransferase inhibitors Trichostatin A and Mocetinostat differentially regulate MMP9, IL-18 and RECK expression, and attenuate Angiotensin II-induced cardiac fibroblast migration and proliferation

Differentiation of atrial fibroblasts into myofibroblasts plays a critical role in atrial fibrosis. Sodium tanshinone IIA sulfonate (DS-201), a water-soluble derivative of tanshinone IIA, has been shown to have potent antifibrotic properties. However, the protective effects of DS-201 on angiotensin II- (Ang II-) induced differentiation of atrial fibroblasts into myofibroblasts remain to be elucidated. In this study, human atrial fibroblasts were stimulated with Ang II in the presence or absence of DS-201. Then, α-smooth muscle actin (α-SMA), collagen I, and collagen III expression and reactive oxygen species (ROS) generation were measured. The expression of transforming growth factor-β1 (TGF-β1) and the downstream signaling of TGF-β1, such as phosphorylation of Smad2/3, were also determined. The results demonstrated that DS-201 significantly prevented Ang II-induced human atrial fibroblast migration and decreased Ang II-induced α-SMA, collagen I, and collagen III expression. Furthermore, increased production of ROS and expression of TGF-β1 stimulated by Ang II were also significantly inhibited by DS-201. Consistent with these results, DS-201 significantly inhibited Ang II-evoked Smad2/3 phosphorylation and periostin expression. These results and the experiments involving N-acetyl cysteine (antioxidant) and an anti-TGF-β1 antibody suggest that DS-201 prevent Ang II-induced differentiation of atrial fibroblasts to myofibroblasts, at least in part, through suppressing oxidative stress and inhibiting the activation of TGF-β1 signaling pathway. All of these data indicate the potential utility of DS-201 for the treatment of cardiac fibrosis.

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MicroRNA‑144 regulates angiotensin II‑induced cardiac fibroblast activation by targeting CREB

Experimental and Therapeutic Medicine ◽

10.3892/etm.2020.8901 ◽

2020 ◽

Author(s):

Zhi‑Yong Liu ◽

Mingjun Lu ◽

Jing Liu ◽

Zhao‑Ning Wang ◽

Wei‑Wei Wang ◽

...

Keyword(s):

Angiotensin Ii ◽

Cardiac Fibroblast ◽

Fibroblast Activation

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Upregulation of α8β1-integrin in cardiac fibroblast by angiotensin II and transforming growth factor-β1

AJP Cell Physiology ◽

10.1152/ajpcell.2001.281.5.c1457 ◽

2001 ◽

Vol 281 (5) ◽

pp. C1457-C1467 ◽

Cited By ~ 32

Author(s):

Gaétan Thibault ◽

Marie-Josée Lacombe ◽

Lynn M. Schnapp ◽

Alexandre Lacasse ◽

Fatiha Bouzeghrane ◽

...

Keyword(s):

Angiotensin Ii ◽

Growth Factor ◽

Matrix Protein ◽

Transforming Growth Factor ◽

Cardiac Fibroblasts ◽

Transforming Growth Factor Β1 ◽

Cardiac Fibroblast ◽

Extracellular Matrix Protein ◽

Ang Ii ◽

Tgf Β1

Using a novel pharmacological tool with125I-echistatin to detect integrins on the cell, we have observed that cardiac fibroblasts harbor five different RGD-binding integrins: α8β1, α3β1, α5β1, αvβ1, and αvβ3. Stimulation of cardiac fibroblasts by angiotensin II (ANG II) or transforming growth factor-β1 (TGF-β1) resulted in an increase of protein and heightening by 50% of the receptor density of α8β1-integrin. The effect of ANG II was blocked by an AT1, but not an AT2, receptor antagonist, or by an anti-TGF-β1 antibody. ANG II and TGF-β1 increased fibronectin secretion, smooth muscle α-actin synthesis, and formation of actin stress fibers and enhanced attachment of fibroblasts to a fibronectin matrix. The α8- and β1-subunits were colocalized by immunocytochemistry with vinculin or β3-integrin at focal adhesion sites. These results indicate that α8β1-integrin is an abundant integrin on rat cardiac fibroblasts. Its positive modulation by ANG II and TGF-β1 in a myofibroblast-like phenotype suggests the involvement of α8β1-integrin in extracellular matrix protein deposition and cardiac fibroblast adhesion.

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223 ADRENERGIC REGULATION OF CARDIAC FIBROBLAST MIGRATION.

Journal of Investigative Medicine ◽

10.1136/jim-52-suppl1-223 ◽

2004 ◽

Vol 52 (Suppl 1) ◽

pp. S118.2-S118

Author(s):

R. E. Laird ◽

M. D. Mitchell ◽

R. D. Brown ◽

C. S. Long

Keyword(s):

Cardiac Fibroblast ◽

Adrenergic Regulation ◽

Fibroblast Migration

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Angiotensin II modulates nitric oxide-induced cardiac fibroblast apoptosis by activation of AKT/PKB

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.01139.2002 ◽

2003 ◽

Vol 285 (3) ◽

pp. H1105-H1112 ◽

Cited By ~ 36

Author(s):

Bin Tian ◽

Jian Liu ◽

Peter Bitterman ◽

Robert J. Bache

Keyword(s):

Nitric Oxide ◽

Angiotensin Ii ◽

Cardiac Fibroblast ◽

Inos Expression ◽

No Production ◽

Ang Ii ◽

Phosphatidylinositol 3 Kinase ◽

No Donor ◽

At1 Antagonist ◽

Phosphatidylinositol 3

Previously we found that interleukin-1β (IL-1β)-activated inducible nitric oxide (NO) synthase (iNOS) expression and that NO production can trigger cardiac fibroblast (CFb) apoptosis. Here, we provide evidence that angiotensin II (ANG II) significantly attenuated IL-1β-induced iNOS expression and NO production in CFbs while simultaneously decreasing apoptotic frequency. The anti-apoptotic effect of ANG II was abolished when cells were pretreated with the specific ANG II type 1 receptor (AT1) antagonist losartan, but not by the AT2 antagonist DP-123319. Furthermore, ANG II also protected CFbs from apoptosis induced by the NO donor diethylenetriamine NONOate and this effect was associated with phosphorylation of Akt/protein kinase B at Ser473. The effects of ANG II on Akt phosphorylation and NO donor-induced CFb apoptosis were abrogated when cells were preincubated with the specific phosphatidylinositol 3-kinase inhibitors wortmannin or LY-294002. These data demonstrate that ANG II protection of CFbs from IL-1β-induced apoptosis is associated with downregulation of iNOS expression and requires an intact phosphatidylinositol 3-kinase-Akt survival signal pathway. The findings suggest that ANG II and NO may play a role in regulating the cell population size by their countervailing influences on cardiac fibroblast viability.

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