All-trans retinoic acid prevents development of cardiac remodeling in aortic banded rats by inhibiting the renin-angiotensin system

This study was designed to determine the effect of all- trans retinoic acid (RA) on the development of cardiac remodeling in a pressure overload rat model. Male Sprague-Dawley rats were subjected to sham operation and the aortic constriction procedure. A subgroup of sham control and aortic constricted rats were treated with RA for 5 mo after surgery. Pressure-overloaded rats showed significantly increased interstitial and perivascular fibrosis, heart weight-to-body weight ratio, and gene expression of atrial natriuretic peptide and brain natriuretic peptide. Echocardiographic analysis showed that pressure overload induced systolic and diastolic dysfunction, as evidenced by decreased fractional shortening, ejection fraction, stroke volume, and increased E-to-Ea ratio and isovolumic relaxation time. RA treatment prevented the above changes in cardiac structure and function and hypertrophic gene expression in pressure-overloaded rats. RA restored the ratio of Bcl-2 to Bax, inhibited cleavage of caspase-3 and -9, and prevented the decreases in the levels of SOD-1 and SOD-2. Pressure overload-induced phosphorylation of ERK1/2, JNK, and p38 was inhibited by RA, via upregulation of mitogen-activated protein kinase phosphatase (MKP)-1 and MKP-2. The pressure overload-induced production of angiotensin II was inhibited by RA via upregulation of expression of angiotensin-converting enzyme (ACE)2 and through inhibition of the expression of cardiac and renal renin, angiotensinogen, ACE, and angiotensin type 1 receptor. Similar results were observed in cultured neonatal cardiomyocytes in response to static stretch. These results demonstrate that RA has a significant inhibitory effect on pressure overload-induced cardiac remodeling, through inhibition of the expression of renin-angiotensin system components.

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Effects of all-trans retinoic acid on renin-angiotensin system in rats with experimental nephritis

AJP Renal Physiology ◽

10.1152/ajprenal.2001.281.5.f909 ◽

2001 ◽

Vol 281 (5) ◽

pp. F909-F919 ◽

Cited By ~ 37

Author(s):

Claudius Dechow ◽

Christian Morath ◽

Jörg Peters ◽

Ingo Lehrke ◽

Rüdiger Waldherr ◽

...

Keyword(s):

Retinoic Acid ◽

Protein Expression ◽

Renin Angiotensin System ◽

Receptor Expression ◽

Nuclear Antigen ◽

Angiotensin System ◽

Renin Angiotensin ◽

Trans Retinoic Acid ◽

All Trans Retinoic Acid ◽

Gene And Protein Expression

We previously demonstrated that all- trans retinoic acid (RA) preserves glomerular structure and function in anti-Thy1.1 nephritis (Wagner J, Dechow C, Morath C, Lehrke I, Amann K, Floege J, and Ritz E. J Am Soc Nephrol 11: 1479–1489, 2000). Because the renin-angiotensin system (RAS) contributes to renal damage, we 1) studied retinoid-specific effects on its components and 2) compared the effects of all- trans-RA with those of the AT1-receptor blocker candesartan. Rats were pretreated for 3 days before injection of the OX-7 antibody and continued with treatment with either vehicle or daily injections of 10 mg/kg all- trans-RA only ( study 1) or 10 mg/kg body wt all- trans-RA, 1 mg/kg candesartan, or both ( study 2) for an additional 7 days. The blood pressure increase observed in anti-Thy1.1 nephritic rats was equally normalized by all- trans-RA and candesartan ( P < 0.05). In nephritic rats, mRNAs of angiotensinogen and angiotensin-converting enzyme (ACE) in the kidney were unchanged, but renin mRNA was lower ( P < 0.01). Renal and glomerular AT1-receptor gene and protein expression levels were higher in anti-Thy1.1 nephritic rats ( P < 0.05). In the renal cortex of nephritic rats, pretreatment with all- trans-RA significantly reduced mRNAs of all the examined RAS components, but in the glomeruli it increased ACE gene and protein expression ( P < 0.01). In nephritic rats, candesartan reduced the number of glomerular cells and mitoses ( P < 0.05) less efficiently than all- trans-RA ( P < 0.01). Both substances reduced cellular proliferation (proliferating cell nuclear antigen) significantly ( P < 0.05). No additive effects were noted when both compounds were combined. In conclusion, all- trans-RA influences the renal RAS in anti-Thy1.1 nephritis by decreasing ANG II synthesis and receptor expression. The beneficial effect of retinoids may be explained, at least in part, by reduction of RAS activity.

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Increased natriuretic peptide receptor A and C gene expression in rats with pressure-overload cardiac hypertrophy

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00612.2005 ◽

2006 ◽

Vol 290 (4) ◽

pp. H1635-H1641 ◽

Cited By ~ 16

Author(s):

Tue E. H. Christoffersen ◽

Mark Aplin ◽

Claes C. Strom ◽

Soren P. Sheikh ◽

Ole Skott ◽

...

Keyword(s):

Gene Expression ◽

Left Ventricle ◽

Cardiac Hypertrophy ◽

Natriuretic Peptide ◽

Pressure Overload ◽

Renin Angiotensin System ◽

Left Ventricular ◽

Natriuretic Peptide Receptor ◽

Angiotensin System ◽

Peptide Receptor

Both atrial (ANP) and brain (BNP) natriuretic peptide affect development of cardiac hypertrophy and fibrosis via binding to natriuretic peptide receptor (NPR)-A in the heart. A putative clearance receptor, NPR-C, is believed to regulate cardiac levels of ANP and BNP. The renin-angiotensin system also affects cardiac hypertrophy and fibrosis. In this study we examined the expression of genes for the NPRs in rats with pressure-overload cardiac hypertrophy. The ANG II type 1 receptor was blocked with losartan (10 mg·kg−1·day−1) to investigate a possible role of the renin-angiotensin system in regulation of natriuretic peptide and NPR gene expression. The ascending aorta was banded in 84 rats during Hypnorm/Dormicum-isoflurane anesthesia; after 4 wk the rats were randomized to treatment with losartan or placebo. The left ventricle of the heart was removed 1, 2, or 4 wk later. Aortic banding increased left ventricular expression of NPR-A and NPR-C mRNA by 110% ( P < 0.001) and 520% ( P < 0.01), respectively, after 8 wk; as expected, it also increased the expression of ANP and BNP mRNAs. Losartan induced a slight reduction of left ventricular weight but did not affect the expression of mRNAs for the natriuretic peptides or their receptors. Although increased gene expression does not necessarily convey a higher concentration of the protein, the data suggest that pressure overload is accompanied by upregulation of not only ANP and BNP but also their receptors NPR-A and NPR-C in the left ventricle.

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Upregulation of Guanylyl Cyclase/Natriuretic Peptide Receptor‐A Gene Expression by All‐trans Retinoic Acid Signaling

The FASEB Journal ◽

10.1096/fasebj.23.1_supplement.1026.7 ◽

2009 ◽

Vol 23 (S1) ◽

Author(s):

Prerna Kumar ◽

Gevoni Bolden ◽

Kailash N. Pandey

Keyword(s):

Gene Expression ◽

Retinoic Acid ◽

Natriuretic Peptide ◽

Guanylyl Cyclase ◽

Natriuretic Peptide Receptor ◽

Retinoic Acid Signaling ◽

Peptide Receptor ◽

Trans Retinoic Acid ◽

All Trans Retinoic Acid ◽

Natriuretic Peptide Receptor A

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Cardiac remodeling during and after renin–angiotensin system stimulation in Cyp1a1-Ren2 transgenic rats

Journal of the Renin-Angiotensin-Aldosterone System ◽

10.1177/1470320313480537 ◽

2013 ◽

Vol 15 (1) ◽

pp. 69-81 ◽

Cited By ~ 5

Author(s):

Bart FJ Heijnen ◽

Leonie PJ Pelkmans ◽

AH Jan Danser ◽

Ingrid M Garrelds ◽

John J Mullins ◽

...

Keyword(s):

Cardiac Remodeling ◽

Renin Angiotensin System ◽

Transgenic Rats ◽

Angiotensin System ◽

Renin Angiotensin

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DNA Methylation Predicts the Response of Triple-Negative Breast Cancers to All-Trans Retinoic Acid

Cancers ◽

10.3390/cancers10110397 ◽

2018 ◽

Vol 10 (11) ◽

pp. 397 ◽

Cited By ~ 11

Author(s):

Krysta Coyle ◽

Cheryl Dean ◽

Margaret Thomas ◽

Dejan Vidovic ◽

Carman Giacomantonio ◽

...

Keyword(s):

Gene Expression ◽

Dna Methylation ◽

Retinoic Acid ◽

Cell Lines ◽

Triple Negative ◽

Atra Treatment ◽

Response Elements ◽

Acid Binding Protein ◽

Trans Retinoic Acid ◽

All Trans Retinoic Acid

All-trans retinoic acid (atRA) regulates gene expression and is used to treat acute promyelocytic leukemia. Attempts to use atRA in breast cancer without a stratification strategy have resulted in limited overall effectiveness. To identify biomarkers for the treatment of triple-negative breast cancer (TNBC) with atRA, we characterized the effects of atRA on the tumor growth of 13 TNBC cell lines. This resulted in a range of effects that was not predictable based on previously hypothesized predictors of response, such as the levels of atRA nuclear shuttling proteins fatty acid binding protein 5 (FABP5) and cellular retinoic acid binding protein 2 (CRABP2). Transcriptional profiling revealed that atRA induced distinct gene expression changes in the sensitive versus resistant cell lines that were mostly independent of the presence of retinoic acid response elements (RAREs) or peroxisome proliferator response elements (PPREs). Given the importance of DNA methylation in regulating gene expression, we hypothesized that differential DNA methylation could predict the response of TNBCs to atRA. We identified over 1400 sites that were differentially methylated between atRA resistant and sensitive cell lines. These CpG sites predicted the response of four TNBC patient-derived xenografts to atRA, and we utilized these xenografts to refine the profile and identified that as many as 17% of TNBC patients could benefit from atRA treatment. These data illustrate that differential methylation of specific CpGs may be useful biomarkers for predicting the response of patient tumors to atRA treatment.

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