Abstract P252: Smooth Muscle At1a Receptor Mediates Perivascular Fibrosis In Angiotensin Ii-infused Mice

Angiotensin II (Ang II) signaling via AT1 receptor has been shown to play a critical role in the pathogenesis of hypertension, cardiovascular hypertrophy and fibrosis. We have demonstrated that ADAM17 expressed in vascular smooth muscle cells (VSMC) mediates EGF receptor activation and promotes cardiac hypertrophy and perivascular fibrosis induced by Ang II. It is conceivable that Ang II signaling in VSMCs specifically initiates cardiovascular remodeling, such as hypertrophy and fibrosis. In a recent study, deficiency of smooth muscle AT1a receptors results in diminished hypertension and protection from cardiac hypertrophy induced by Ang II. However, we have limited understanding whether smooth muscle AT1a receptors affects hypertensive fibrosis in vasculature. Thus, this study was designed to elucidate the roles of the AT1a receptor in VSMCs in cardiovascular remodeling including fibrosis during Ang II stimulation using VSMC AT1a receptor deficient mice. To delete the AT1a receptor from VSMCs, we crossed C57BL/6 transgenic mouse lines expressing Cre recombinase under the control of the sm22α promoter (KIsm22α-Cre). Male AT1a flox/flox KIsm22α-Cre+/- (SMKO) and Controls (AT1a flox/flox KIsm22α-Cre-/-) mice were infused with Ang II (1 μg/kg/min) for 2 weeks via osmotic mini-pump. In Control mice, Ang II infusion for 2 weeks induced cardiac hypertrophy indicated by heart-to-body weight ratio and echocardiogram. After 2 weeks of Ang II infusion, heart-to-body weight ratios were significantly increased in Control mice compared with AT1a SMKO mice (6.04 versus 4.89, respectively, p=0.032). Cardiac wall hypertrophy was seen in Controls after 2 weeks of Ang II infusion, which was attenuated in AT1a SMKOs. Control mice (n=5) showed vascular medial hypertrophy and perivascular fibrosis, whereas these phenotypic changes were attenuated in SMKO mice (n=4). In conclusion, AT1a receptors from VSMC could mediate Ang II-induced cardiovascular hypertrophy and perivascular fibrosis. Whether the data can be fully explained by the prevention of hypertension remains to be determined, the data contrast to the past manuscript showing a protective effect in AT1a flox/flox S100A4-Cre+/- mice (fibroblast silencing) with Ang II infusion.

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Abstract 47: Caveolin-1 is Critical for Abdominal Aortic Aneurysm Induced by Angiotensin II

Hypertension ◽

10.1161/hyp.62.suppl_1.a47 ◽

2013 ◽

Vol 62 (suppl_1) ◽

Author(s):

Takashi Obama ◽

Takehiko Takayanagi ◽

Kevin J Crawford ◽

Tomonori Kobayashi ◽

Victor Rizzo ◽

...

Keyword(s):

Oxidative Stress ◽

Smooth Muscle ◽

Abdominal Aortic Aneurysm ◽

Angiotensin Ii ◽

Aortic Aneurysm ◽

Vascular Smooth Muscle Cells ◽

Critical Role ◽

Ang Ii ◽

Caveolin 1 ◽

Abdominal Aortic

Abdominal aortic aneurysm (AAA) is a significant cause of mortality for adults aged >60 years. Accumulating evidence suggests a role of angiotensin II (Ang II) in abdominal aortic aneurysm (AAA) formation. However, the Ang II-sensitive proximal signaling events primarily responsible for AAA formation remain unclear. We recently reported that caveolin-1 (Cav1) enriched membrane microdomains in vascular smooth muscle cells (VSMC) mediate a metalloprotease ADAM17-dependent EGF receptor (EGFR) transactivation, which is linked to vascular remodeling induced by Ang II. Given that ADAM17 expression is one of the key features in AAA, we have tested our hypothesis that Cav1, a major structural protein of caveolae, plays a critical role for development of AAA by Ang II via regulation of ADAM17. 8 week old male Cav1-/- and the control C57Bl/6 wild-type mice (WT) were co-infused with Ang II (1 μg/kg/min) and β-aminopropionitrile (BAPN: 150mg/kg/day) for 4 weeks to induce AAA. In WT with the co-infusion, 58% (14/24) were dead due to aortic rupture/dissection. All surviving WT with co-infusion had AAA with max diameter (mm) of 2.6±0.18 vs 0.93±0.09 with saline infusion (p<0.01). In contrast, we found that Cav1-/- with co-infusion did not die or develop AAA. The max diameter (mm) of AAA in Cav1-/- with co-infusion was 1.0±0.04 vs 1.1±0.06 with saline infusion (n=7). In contrast, both WT and Cav1-/- with the co-infusion developed hypertension assessed by telemetry (MAP mmHg: 151±5 vs 161±7). We found an increased expression of ADAM17 by IHC and qPCR, and enhanced phosphorylation of EGFR by IHC in WT abdominal aortae with aneurysms. These events were markedly attenuated in Cav1-/- aorta with co-infusion (ADAM17/18S mRNAx10,000 = 3.08±0.71 vs 0.97±0.42 p<0.05, n=4). Furthermore, Cav1-/- aortae showed less ER and oxidative stress compared to WT aortae assessed by IHC. In addition, Cav1 silencing induced by adenovirus encoding Cav1 targeting siRNA embedded miRNA in cultured vascular smooth muscle cells prevented Ang II-induced ADAM17 induction and activation. In conclusion, Cav1 and presumably vascular caveolae microdomains appear to play a critical role in the formation of AAA by Ang II via regulation of the ADAM17/EGFR signaling and subsequent ER/oxidative stress.

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Abstract 3551: Cyclophilin a Promotes Angiotensin II-Induced Inflammation and Cardiovascular Hypertrophy in Mice

Circulation ◽

10.1161/circ.118.suppl_18.s_442-b ◽

2008 ◽

Vol 118 (suppl_18) ◽

Author(s):

Kimio Satoh ◽

Liam Casey ◽

Michael R O’Dell ◽

Patrizia Nigro ◽

Amy Mohan ◽

...

Keyword(s):

Body Weight ◽

Angiotensin Ii ◽

Cardiac Hypertrophy ◽

Rhode Island ◽

Bone Marrow Cells ◽

Weight Ratio ◽

Cyclophilin A ◽

Ros Production ◽

Body Weight Ratio ◽

Cardiovascular Hypertrophy

Background - Cyclophilin A (CyPA) is a chaperone protein secreted from vascular smooth muscle cells (VSMC) in response to reactive oxygen species (ROS). We have recently demonstrated that extracellular CyPA stimulates at least 3 signaling pathways (ERK1/2, Akt and JAK) and mediates numerous cellular effects of ROS. Angiotensin II (Ang II) induces ROS through NADPH oxidases and activates matrix metalloproteinase (MMP) in VSMC. ROS and MMPs have been demonstrated to mediate cardiac hypertrophy and remodeling. We hypothesized that VSMC-derived CyPA contributes to AngII-induced cardiovascular hypertrophy in vivo due to its proinflammatory properties. Methods and Results - ApoE −/− and ApoE −/− CyPA −/− mice were treated with AngII (1000 ng/min/kg for 4 weeks) to induce cardiac hypertrophy. Long-term infusion of AngII significantly increased heart/body weight ratio in ApoE −/− mice, which was significantly less in ApoE −/− CyPA −/− mice (6.6±1.0 vs. 4.8±0.7, P <0.01). Echocar-diography confirmed a significantly greater increase in LV mass in ApoE −/− mice compared to ApoE −/− CyPA −/− mice (112% vs. 47%). Perivascular accumulation of inflammatory cells and cardiac myofibroblasts in ApoE −/− mice was significantly greater than in ApoE −/− CyPA −/− mice. Consequently, coronary artery ROS production (DHE fluorescence) and MMP activation (in situ zymography) were markedly increased by AngII in ApoE −/− mice compared to ApoE −/− CyPA −/− mice. To determine the source of CyPA, bone marrow cells (BMCs) transplantation was performed. The heart/body weight ratio was still higher in ApoE −/− mice compared with ApoE −/− CyPA −/− mice after reconstitution with GFP + CyPA +/+ BMCs (6.7±0.6 vs. 5.6±0.9, P <0.01). Recruitment of GFP + BMCs to the heart in chimeric ApoE −/− mice was significantly greater than the chimeric ApoE −/− CyPA −/− mice (count/area; 218±63 vs. 109±43, P <0.01). To prove a vascular source of CyPA was essential, VSMC-specific CyPA overexpressing mice were generated. In these mice there was a significant increase in cardiac MMP activity after AngII infusion (VSMC-Tg > WT > CyPA −/− ). Conclusion - CyPA is a novel mediator of AngII-induced cardiac hypertrophy by stimulating vascular ROS production, MMP activation, and inflammatory cell recruitment. This research has received full or partial funding support from the American Heart Association, AHA Founders Affiliate (Connecticut, Maine, Massachusetts, New Hampshire, New Jersey, New York, Rhode Island, Vermont).

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AT1 and AT2 receptors modulate renal tubular cell necroptosis in angiotensin II-infused renal injury mice

Scientific Reports ◽

10.1038/s41598-019-55550-8 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 4

Author(s):

Yongjun Zhu ◽

Hongwang Cui ◽

Jie Lv ◽

Haiqin Liang ◽

Yanping Zheng ◽

...

Keyword(s):

Angiotensin Ii ◽

Renal Injury ◽

Critical Role ◽

Kidney Injury ◽

Renin Angiotensin System ◽

Tubular Cell ◽

Tubular Damage ◽

Renal Tubular Cell ◽

Ang Ii ◽

Renal Tubular

AbstractAbnormal renin-angiotensin system (RAS) activation plays a critical role in the initiation and progression of chronic kidney disease (CKD) by directly mediating renal tubular cell apoptosis. Our previous study showed that necroptosis may play a more important role than apoptosis in mediating renal tubular cell loss in chronic renal injury rats, but the mechanism involved remains unknown. Here, we investigate whether blocking the angiotensin II type 1 receptor (AT1R) and/or angiotensin II type 2 receptor (AT2R) beneficially alleviates renal tubular cell necroptosis and chronic kidney injury. In an angiotensin II (Ang II)-induced renal injury mouse model, we found that blocking AT1R and AT2R effectively mitigates Ang II-induced increases in necroptotic tubular epithelial cell percentages, necroptosis-related RIP3 and MLKL protein expression, serum creatinine and blood urea nitrogen levels, and tubular damage scores. Furthermore, inhibition of AT1R and AT2R diminishes Ang II-induced necroptosis in HK-2 cells and the AT2 agonist CGP42112A increases the percentage of necroptotic HK-2 cells. In addition, the current study also demonstrates that Losartan and PD123319 effectively mitigated the Ang II-induced increases in Fas and FasL signaling molecule expression. Importantly, disruption of FasL significantly suppressed Ang II-induced increases in necroptotic HK-2 cell percentages, and necroptosis-related proteins. These results suggest that Fas and FasL, as subsequent signaling molecules of AT1R and AT2R, might involve in Ang II-induced necroptosis. Taken together, our results suggest that Ang II-induced necroptosis of renal tubular cell might be involved both AT1R and AT2R and the subsequent expression of Fas, FasL signaling. Thus, AT1R and AT2R might function as critical mediators.

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Oxidative Stress as A Mechanism for Functional Alterations in Cardiac Hypertrophy and Heart Failure

Antioxidants ◽

10.3390/antiox10060931 ◽

2021 ◽

Vol 10 (6) ◽

pp. 931

Author(s):

Anureet K. Shah ◽

Sukhwinder K. Bhullar ◽

Vijayan Elimban ◽

Naranjan S. Dhalla

Keyword(s):

Oxidative Stress ◽

Heart Failure ◽

Angiotensin Ii ◽

Cardiac Hypertrophy ◽

Cardiac Remodeling ◽

Cardiac Dysfunction ◽

Critical Role ◽

Pressure Overload ◽

Hypertrophied Heart ◽

Vasoactive Hormones

Although heart failure due to a wide variety of pathological stimuli including myocardial infarction, pressure overload and volume overload is associated with cardiac hypertrophy, the exact reasons for the transition of cardiac hypertrophy to heart failure are not well defined. Since circulating levels of several vasoactive hormones including catecholamines, angiotensin II, and endothelins are elevated under pathological conditions, it has been suggested that these vasoactive hormones may be involved in the development of both cardiac hypertrophy and heart failure. At initial stages of pathological stimuli, these hormones induce an increase in ventricular wall tension by acting through their respective receptor-mediated signal transduction systems and result in the development of cardiac hypertrophy. Some oxyradicals formed at initial stages are also involved in the redox-dependent activation of the hypertrophic process but these are rapidly removed by increased content of antioxidants in hypertrophied heart. In fact, cardiac hypertrophy is considered to be an adaptive process as it exhibits either normal or augmented cardiac function for maintaining cardiovascular homeostasis. However, exposure of a hypertrophied heart to elevated levels of circulating hormones due to pathological stimuli over a prolonged period results in cardiac dysfunction and development of heart failure involving a complex set of mechanisms. It has been demonstrated that different cardiovascular abnormalities such as functional hypoxia, metabolic derangements, uncoupling of mitochondrial electron transport, and inflammation produce oxidative stress in the hypertrophied failing hearts. In addition, oxidation of catecholamines by monoamine oxidase as well as NADPH oxidase activation by angiotensin II and endothelin promote the generation of oxidative stress during the prolonged period by these pathological stimuli. It is noteworthy that oxidative stress is known to activate metallomatrix proteases and degrade the extracellular matrix proteins for the induction of cardiac remodeling and heart dysfunction. Furthermore, oxidative stress has been shown to induce subcellular remodeling and Ca2+-handling abnormalities as well as loss of cardiomyocytes due to the development of apoptosis, necrosis, and fibrosis. These observations support the view that a low amount of oxyradical formation for a brief period may activate redox-sensitive mechanisms, which are associated with the development of cardiac hypertrophy. On the other hand, high levels of oxyradicals over a prolonged period may induce oxidative stress and cause Ca2+-handling defects as well as protease activation and thus play a critical role in the development of adverse cardiac remodeling and cardiac dysfunction as well as progression of heart failure.

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Lipid signal transduction pathways in angiotensin II type 1 receptor-transfected fibroblasts

AJP Cell Physiology ◽

10.1152/ajpcell.1995.269.2.c435 ◽

1995 ◽

Vol 269 (2) ◽

pp. C435-C442 ◽

Cited By ~ 19

Author(s):

Y. Wen ◽

M. C. Cabot ◽

E. Clauser ◽

S. L. Bursten ◽

J. L. Nadler

Keyword(s):

Signal Transduction ◽

Angiotensin Ii ◽

Chinese Hamster ◽

Receptor Activation ◽

Signal Transduction Pathways ◽

Ang Ii ◽

Vascular Type ◽

Lipid Signal ◽

Fibroblast Line

A stable Chinese hamster ovary fibroblast line expressing the rat vascular type 1a angiotensin II (ANG II) receptor was used to study the lipid-derived signal transduction pathways elicited by type 1a ANG II receptor activation. ANG II caused a biphasic and dose-dependent increase in diacylglycerol (DAG) accumulation with an initial peak at 15 s (181 +/- 11% of control, P < 0.02) and a second sustained peak at 5-10 min (214 +/- 10% of control, P < 0.02). The late DAG peak was derived from phosphatidylcholine (PC), and the formation was blocked by ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid. ANG II also increased phosphatidic acid (PA) production nearly fourfold by 7.5 min. In the presence of ethanol, ANG II markedly increased phosphatidylethanol (PEt) formation, indicating activation of phospholipase D (PLD). ANG II was shown to increase the mass of three separate PA species, one of which apparently originated from DAG kinase action on PC-phospholipase C (PLC)-produced DAG, providing evidence for PC-PLC activity. ANG II also formed a third PA species, which originated neither from PLD nor from DAG kinase. These results demonstrate that multiple lipid signals propagated via collateral stimulation of PLC and PLD are generated by specific activation of the vascular type 1a ANG II receptor.

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Vasopressin/V2 receptor stimulates renin synthesis in the collecting duct

AJP Renal Physiology ◽

10.1152/ajprenal.00360.2015 ◽

2016 ◽

Vol 310 (4) ◽

pp. F284-F293 ◽

Cited By ~ 18

Author(s):

Alexis A. Gonzalez ◽

Flavia Cifuentes-Araneda ◽

Cristobal Ibaceta-Gonzalez ◽

Alex Gonzalez-Vergara ◽

Leonardo Zamora ◽

...

Keyword(s):

Collecting Duct ◽

Critical Role ◽

Combined Treatment ◽

Receptor Activation ◽

Ang Ii ◽

Principal Cells ◽

Protein Levels ◽

Renin Synthesis ◽

Renin Mrna ◽

Creb Pathway

Renin is synthesized in the principal cells of the collecting duct (CD), and its production is increased via cAMP in angiotensin (ANG) II-dependent hypertension, despite suppression of juxtaglomerular (JG) renin. Vasopressin, one of the effector hormones of the renin-angiotensin system (RAS) via the type 2-receptor (V2R), activates the cAMP/PKA/cAMP response element-binding protein (CREB) pathway and aquaporin-2 expression in principal cells of the CD. Accordingly, we hypothesized that activation of V2R increases renin synthesis via PKA/CREB, independently of ANG II type 1 (AT1) receptor activation in CD cells. Desmopressin (DDAVP; 10−6 M), a selective V2R agonist, increased renin mRNA (∼3-fold), prorenin (∼1.5-fold), and renin (∼2-fold) in cell lysates and cell culture media in the M-1 CD cell line. Cotreatment with DDAVP+H89 (PKA inhibitor) or CREB short hairpin (sh) RNA prevented this response. H89 also blunted DDAVP-induced CREB phosphorylation and nuclear localization. In 48-h water-deprived (WD) mice, prorenin-renin protein levels were increased in the renal inner medulla (∼1.4- and 1.8-fold). In WD mice treated with an ACE inhibitor plus AT1 receptor blockade, renin mRNA and prorenin protein levels were still higher than controls, while renin protein content was not changed. In M-1 cells, ANG II or DDAVP increased prorenin-renin protein levels; however, there were no further increases by combined treatment. These results indicate that in the CD the activation of the V2R stimulates renin synthesis via the PKA/CREB pathway independently of RAS, suggesting a critical role for vasopressin in the regulation of renin in the CD.

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Angiotensin II modulates frizzled-2 receptor expression in rat vascular smooth muscle cells

Clinical Science ◽

10.1042/cs20040347 ◽

2005 ◽

Vol 108 (6) ◽

pp. 523-530 ◽

Cited By ~ 5

Author(s):

Giovanna CASTOLDI ◽

Serena REDAELLI ◽

Willy M. M. van de GREEF ◽

Cira R. T. di GIOIA ◽

Giuseppe BUSCA ◽

...

Keyword(s):

Smooth Muscle ◽

Angiotensin Ii ◽

Vascular Smooth Muscle ◽

Smooth Muscle Cells ◽

Vascular Smooth Muscle Cells ◽

Muscle Cells ◽

Ang Ii ◽

Aortic Smooth Muscle

Ang II (angiotensin II) has multiple effects on vascular smooth muscle cells through the modulation of different classes of genes. Using the mRNA differential-display method to investigate gene expression in rat aortic smooth muscle cells in culture in response to 3 h of Ang II stimulation, we observed that Ang II down-regulated the expression of a member of the family of transmembrane receptors for Wnt proteins that was identified as Fzd2 [Fzd (frizzled)-2 receptor]. Fzds are a class of highly conserved genes playing a fundamental role in the developmental processes. In vitro, time course experiments demonstrated that Ang II induced a significant increase (P<0.05) in Fzd2 expression after 30 min, whereas it caused a significant decrease (P<0.05) in Fzd2 expression at 3 h. A similar rapid up-regulation after Ang II stimulation for 30 min was evident for TGFβ1 (transforming growth factor β1; P<0.05). To investigate whether Ang II also modulated Fzd2 expression in vivo, exogenous Ang II was administered to Sprague–Dawley rats (200 ng·kg−1 of body weight·min−1; subcutaneously) for 1 and 4 weeks. Control rats received normal saline. After treatment, systolic blood pressure was significantly higher (P<0.01), whereas plasma renin activity was suppressed (P<0.01) in Ang II- compared with the saline-treated rats. Ang II administration for 1 week did not modify Fzd2 expression in aorta of Ang II-treated rats, whereas Ang II administration for 4 weeks increased Fzd2 mRNA expression (P<0.05) in the tunica media of the aorta, resulting in a positive immunostaining for fibronectin at this time point. In conclusion, our data demonstrate that Ang II modulates Fzd2 expression in aortic smooth muscle cells both in vitro and in vivo.

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Capn4 aggravates angiotensin II-induced cardiac hypertrophy by activating the IGF-AKT signaling pathway

The Journal of Biochemistry ◽

10.1093/jb/mvab100 ◽

2021 ◽

Author(s):

Yuanping Cao ◽

Qun Wang ◽

Caiyun Liu ◽

Wenjun Wang ◽

Songqing Lai ◽

...

Keyword(s):

Angiotensin Ii ◽

Cardiac Hypertrophy ◽

Signaling Pathway ◽

Expression Patterns ◽

Akt Signaling ◽

Calpain Inhibitor ◽

Ang Ii ◽

Akt Signaling Pathway ◽

Calpain Activity

Abstract Capn4 belongs to a family of calpains that participate in a wide variety of biological functions, but little is known about the role of Capn4 in cardiac disease. Here, we show that the expression of Capn4 was significantly increased in Angiotensin II (Ang II)-treated cardiomyocytes and Ang II-induced cardiac hypertrophic mouse hearts. Importantly, in agreement with the Capn4 expression patterns, the maximal calpain activity measured in heart homogenates was elevated in Ang II-treated mice, and oral coadministration of SNJ-1945 (calpain inhibitor) attenuated the total calpain activity measured in vitro. Functional assays indicated that overexpression of Capn4 obviously aggravated Ang II-induced cardiac hypertrophy, whereas Capn4 knockdown resulted in the opposite phenotypes. Further investigation demonstrated that Capn4 maintained the activation of the insulin-like growth factor (IGF)-AKT signaling pathway in cardiomyocytes by increasing c-Jun expression. Mechanistic investigations revealed that Capn4 directly bound and stabilized c-Jun, and knockdown of Capn4 increased the ubiquitination level of c-Jun in cardiomyocytes. Additionally, our results demonstrated that the antihypertrophic effect of Capn4 silencing was partially dependent on the inhibition of c-Jun. Overall, these data suggested that Capn4 contributes to cardiac hypertrophy by enhancing the c-Jun-mediated IGF-AKT signaling pathway and could be a potential therapeutic target for hypertrophic cardiomyopathy.

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Essential role of PKC-ζ in normal and angiotensin II-accelerated neointimal growth after vascular injury

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.01363.2005 ◽

2006 ◽

Vol 291 (4) ◽

pp. H1602-H1613 ◽

Cited By ~ 12

Author(s):

Jean-Hugues Parmentier ◽

Chunxiang Zhang ◽

Anne Estes ◽

Susan Schaefer ◽

Kafait U. Malik

Keyword(s):

Smooth Muscle ◽

Vascular Injury ◽

Critical Role ◽

Immunohistochemical Analysis ◽

Vascular Wall ◽

Ang Ii ◽

Neointimal Formation ◽

Monocyte Chemoattractant Protein 1 ◽

Perivascular Area ◽

Pkc Ζ

The contribution of atypical protein kinase C (PKC)-ζ to ANG II-accelerated restenosis after endoluminal vascular injury was investigated by using the rat carotid balloon injury model. Exposure of injured arteries to ANG II resulted in an extensive neointimal thickening (1.9 times) compared with vehicle at day 14. Treatment with PKC-ζ antisense, but not scrambled, oligonucleotides reduced neointimal formation observed in the presence or absence of ANG II. Examination of early events (2 days) after injury showed an increase in cellularity in the perivascular area of the artery wall that was transferred to the adventitia and media after exposure to ANG II, events blocked by PKC-ζ antisense, but not scrambled, oligonucleotides. A positive correlation between medial cellularity at day 2 and extent of neointimal growth at day 14 was established. Immunohistochemical analysis showed that upregulation of inflammatory markers after injury, as well as infiltration of ED1+monocytes/macrophages from the perivascular area to the adventitia, was accelerated by ANG II. However, ANG II-stimulated medial increase in cellularity was proliferation independent, and these cells were monocyte chemoattractant protein-1+/vimentin+but ED1−/VCAM−. PKC-ζ is degraded after injury, and inhibition of its neosynthesis in medial vascular smooth muscle cells or in infiltrating cells with PKC-ζ antisense attenuated medial cellularity and expression of inflammation mediators without reversing smooth muscle cell dedifferentiation. Together, these data indicate that PKC-ζ plays a critical role in normal and ANG II-accelerated neointimal growth through a mechanism involving upregulation of inflammatory mediators, leading to cell infiltration in the media of the vascular wall.

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Sodium Tanshinone IIA Sulfonate Prevents Angiotensin II-Induced Differentiation of Human Atrial Fibroblasts into Myofibroblasts

Oxidative Medicine and Cellular Longevity ◽

10.1155/2018/6712585 ◽

2018 ◽

Vol 2018 ◽

pp. 1-10 ◽

Cited By ~ 5

Author(s):

Tangting Chen ◽

Miaoling Li ◽

Xuehui Fan ◽

Jun Cheng ◽

Liqun Wang

Keyword(s):

Angiotensin Ii ◽

Critical Role ◽

Water Soluble ◽

Collagen I ◽

Tanshinone Iia ◽

Ang Ii ◽

Induced Differentiation ◽

Fibroblast Migration ◽

Collagen Iii ◽

Sodium Tanshinone Iia Sulfonate

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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