Ramipril attenuates left ventricular remodeling by regulating the expression of activin A-follistatin in a rat model of heart failure

Qun Wei, Haiyan Liu, Miao Liu, Chunyan Yang, Jie Yang, Zhonghui Liu, Ping Yang, Qun Wei, Haiyan Liu, Miao Liu, Chunyan Yang, Jie Yang, Zhonghui Liu, Ping Yang

Abstract

Prior studies have shown that overexpression of ACT A can lead to ventricular remodeling in rat models of heart failure. Furthermore, recently work studying demonstrated that stimulation of activin An expression in rat aortic smooth muscle (RASM) cells by angiotensin II (Ang II). Ramipril is a recently developed angiotensin converting enzyme (ACE) inhibitor. To investigate the effects of Ramipril on expression of ACT A-FS, we established the rat model of heart failure after myocardial infarction (MI), and divided into either a sham operation (SO), MI, or MI-Ramipril group. We found that Ramipril significantly attenuates collagen-I and III deposition (col-I and III). Notably, we determined that expression of ACT A and II activin receptor (ActRII) were significantly down-regulated in the non-infarcted area of the left ventricle in the Ramipril group, whereas the mRNA and protein levels of FS were markedly up-regulated. Our data suggested that Ramipril benefited left ventricular remodeling by reducing fibrosis and collagen accumulation in the left ventricle of rats after myocardial infarction. This observation was also associated with down-regulation of ACT A expression. This study elucidated a new protective mechanism of Ramipril and suggests a novel strategy for treatment of post-infarct remodeling and subsequent heart failure.

Figures

Figure 1. Morphology of rat hearts.
Figure 1. Morphology of rat hearts.
(A) Gross morphology of hearts of sham-operated rats (SO), ramipril-treated SO rats (SO-ramipril), rats with myocardial infarction (MI) and ramipril-treated MI rats. (B) Hematoxylin and eosin staining of the myocardial tissue in the non-infarcted area of the left ventricle.
Figure 2
Figure 2
Expression of activin A (panel A), ActRIIA (panel B), ActRIIB (panel C), follistatin (panel D), collagen I and collagen III mRNA (panel E), and the ratio of col I to col III (panel F) in the non-infarcted area of the left ventricle detected by semi-quantitative reverse transcription polymerase chain reaction. S represented SO group, S + R represented SO-ramipril, MI represented MI-model, M + R represented MI-ramipril. The depicted data are the means ± SD. *P < 0.05, **P < 0.01, ***P < 0.001 vs S; †P < 0.05, ††P < 0.01, †††P < 0.001vs MI.
Figure 3
Figure 3
Immunohistochemical staining for activin A and follistatin using anti-activin A antibody (B–E) and anti-follistatin antibody (G–J) in the non-infarcted area of the left ventricle. (A,F) represented procedural background control using normal rabbit IgG. (B,H) represented SO group, (C,H) represented SO-ramipril group, (D,I) represented MI-model group, (E,J) represented MI-ramipril group (200× magnification).
Figure 4. Myocaridal fibrosis after myocardial infarction…
Figure 4. Myocaridal fibrosis after myocardial infarction detected by Masson’s trichrome staining in sham-operated rats (SO), ramipril-treated SO rats (SO-ramipril), rats with myocardial infarction (MI) and ramipril-treated MI rats in the noninfarcted area of the left ventricle (200× magnification).

References

    1. Pawlowski J. E. et al. Stimulation of activin A expression in rat aortic smooth muscle cells by thrombin and angiotensin II correlates with neointimal formation in vivo. The Journal of clinical investigation 100, 639–648, doi: 10.1172/jci119575 (1997).
    1. de Kretser D. M., Hedger M. P. & Phillips D. J. Activin A and follistatin: their role in the acute phase reaction and inflammation. The Journal of endocrinology 161, 195–198 (1999).
    1. Werner S. & Alzheimer C. Roles of activin in tissue repair, fibrosis, and inflammatory disease. Cytokine & growth factor reviews 17, 157–171, doi: 10.1016/j.cytogfr.2006.01.001 (2006).
    1. Zhang H. J., Tai G. X., Zhou J., Ma D. & Liu Z. H. Regulation of activin receptor-interacting protein 2 expression in mouse hepatoma Hepa1-6 cells and its relationship with collagen type IV. World journal of gastroenterology 13, 5501–5505 (2007).
    1. Nakamura T. et al. Activin-binding protein from rat ovary is follistatin. Science (New York, N.Y.) 247, 836–838 (1990).
    1. Wakatsuki, M(1) S. Y., Abe M., Liu Z. H., Shitsukawa K. & Saito S. Immunoradiometric assay for follistatin: serum immunoreactive follistatin levels in normal adults and pregnant women. J Clin Endocrinol Metab. 81, 630–634 (1996).
    1. Hashimoto O. et al. A novel role of follistatin, an activin-binding protein, in the inhibition of activin action in rat pituitary cells. Endocytotic degradation of activin and its acceleration by follistatin associated with cell-surface heparan sulfate. The Journal of biological chemistry 272, 13835–13842 (1997).
    1. Yndestad A. et al. Elevated levels of activin A in heart failure: potential role in myocardial remodeling. Circulation 109, 1379–1385, doi: 10.1161/01.cir.0000120704.97934.41 (2004).
    1. Hubner G., Hu Q., Smola H. & Werner S. Strong induction of activin expression after injury suggests an important role of activin in wound repair. Developmental biology 173, 490–498, doi: 10.1006/dbio.1996.0042 (1996).
    1. Cruise B. A., Xu P. & Hall A. K. Wounds increase activin in skin and a vasoactive neuropeptide in sensory ganglia. Developmental biology 271, 1–10, doi: 10.1016/j.ydbio.2004.04.003 (2004).
    1. Munz B. et al. Overexpression of activin A in the skin of transgenic mice reveals new activities of activin in epidermal morphogenesis, dermal fibrosis and wound repair. The EMBO journal 18, 5205–5215, doi: 10.1093/emboj/18.19.5205 (1999).
    1. Wankell M. et al. Impaired wound healing in transgenic mice overexpressing the activin antagonist follistatin in the epidermis. The EMBO journal 20, 5361–5372, doi: 10.1093/emboj/20.19.5361 (2001).
    1. Solomon S. D. et al. Changes in ventricular size and function in patients treated with valsartan, captopril, or both after myocardial infarction. Circulation 111, 3411–3419, doi: 10.1161/circulationaha.104.508093 (2005).
    1. Solomon S. D. et al. Sudden death in patients with myocardial infarction and left ventricular dysfunction, heart failure, or both. The New England journal of medicine 352, 2581–2588, doi: 10.1056/NEJMoa043938 (2005).
    1. Wei Q. et al. The expression and role of activin A and follistatin in heart failure rats after myocardial infarction. International journal of cardiology 168, 2994–2997, doi: 10.1016/j.ijcard.2013.04.012 (2013).
    1. McMurray J. & Pfeffer M. A. New therapeutic options in congestive heart failure: Part II. Circulation 105, 2223–2228 (2002).
    1. Zile M. R. & Brutsaert D. L. New concepts in diastolic dysfunction and diastolic heart failure: Part II: causal mechanisms and treatment. Circulation 105, 1503–1508 (2002).
    1. Peng H. et al. Antifibrotic effects of N-acetyl-seryl-aspartyl-Lysyl-proline on the heart and kidney in aldosterone-salt hypertensive rats. Hypertension 37, 794–800 (2001).
    1. Tayebjee M. H., MacFadyen R. J. & Lip G. Y. Extracellular matrix biology: a new frontier in linking the pathology and therapy of hypertension? Journal of hypertension 21, 2211–2218, doi: 10.1097/01.hjh.0000098178.36890.81 (2003).
    1. Yang F. et al. Ac-SDKP reverses inflammation and fibrosis in rats with heart failure after myocardial infarction. Hypertension 43, 229–236, doi: 10.1161/01.hyp.0000107777.91185.89 (2004).
    1. Ju H., Zhao S., Jassal D. S. & Dixon I. M. Effect of AT1 receptor blockade on cardiac collagen remodeling after myocardial infarction. Cardiovascular research 35, 223–232 (1997).
    1. Beltrami C. A. et al. Structural basis of end-stage failure in ischemic cardiomyopathy in humans. Circulation 89, 151–163 (1994).
    1. Hilfiker-Kleiner D., Landmesser U. & Drexler H. Molecular mechanisms in heart failure: focus on cardiac hypertrophy, inflammation, angiogenesis, and apoptosis. Journal of the American College of Cardiology 48, A56–A66 (2006).
    1. Attisano L., Wrana J. L., Montalvo E. & Massague J. Activation of signalling by the activin receptor complex. Molecular and cellular biology 16, 1066–1073 (1996).
    1. Mathews L. S. & Vale W. W. Expression cloning of an activin receptor, a predicted transmembrane serine kinase. Cell 65, 973–982 (1991).
    1. Tsuchida K., Vaughan J. M., Wiater E., Gaddy-Kurten D. & Vale W. W. Inactivation of activin-dependent transcription by kinase-deficient activin receptors. Endocrinology 136, 5493–5503, doi: 10.1210/endo.136.12.7588300 (1995).
    1. Willis S. A., Zimmerman C. M., Li L. I. & Mathews L. S. Formation and activation by phosphorylation of activin receptor complexes. Molecular endocrinology (Baltimore, Md.) 10, 367–379, doi: 10.1210/mend.10.4.8721982 (1996).
    1. Mathews L. S. Activin receptors and cellular signaling by the receptor serine kinase family. Endocrine reviews 15, 310–325, doi: 10.1210/edrv-15-3-310 (1994).
    1. Attisano L., Silvestri C., Izzi L. & Labbé E. The transcriptional role of Smads and FAST (FoxH1) in TGFβ and activin signalling. Molecular and cellular endocrinology 180, 3–11 (2001).
    1. Heldin C. H., Miyazono K. & ten Dijke P. TGF-beta signalling from cell membrane to nucleus through SMAD proteins. Nature 390, 465–471, doi: 10.1038/37284 (1997).
    1. Liu Z. H. et al. Characterization of isoforms of activin receptor-interacting protein 2 that augment activin signaling. The Journal of endocrinology 189, 409–421, doi: 10.1677/joe.1.06420 (2006).
    1. Lin S. Y., Morrison J. R., Phillips D. J. & de Kretser D. M. Regulation of ovarian function by the TGF-beta superfamily and follistatin. Reproduction (Cambridge, England) 126, 133–148 (2003).
    1. Liu Z. H. et al. Effects of LHRH, FSH and activin A on follistatin secretion from cultured rat anterior pituitary cells. Endocrine journal 43, 321–327 (1996).
    1. Yamashita S., Maeshima A., Kojima I. & Nojima Y. Activin A is a potent activator of renal interstitial fibroblasts. Journal of the American Society of Nephrology: Jasn 15, 91–101 (2004).
    1. Hashimoto M. et al. Functional regulation of osteoblastic cells by the interaction of activin-A with follistatin. The Journal of biological chemistry 267, 4999–5004 (1992).
    1. Inoue S. et al. Demonstration of activin-A in arteriosclerotic lesions. Biochemical and biophysical research communications 205, 441–448, doi: 10.1006/bbrc.1994.2685 (1994).
    1. Molloy C. J., Taylor D. S. & Pawlowski J. E. Novel cardiovascular actions of the activins. The Journal of endocrinology 161, 179–185 (1999).
    1. Zhang L. J. et al. [Study on the expression of activin-A in myocardial ischemia postconditioning]. Sichuan da xue xue bao. Yi xue ban= Journal of Sichuan University. Medical science edition 40, 97–99 (2009).
    1. Lima A. R. et al. Myostatin and follistatin expression in skeletal muscles of rats with chronic heart failure. International journal of experimental pathology 91, 54–62, doi: 10.1111/j.1365-2613.2009.00683.x (2010).
    1. Fukushima N., Matsuura K., Akazawa H. et al.A Crucial Role of Activin A-Mediated Growth Hormone Suppression in Mouse and Human Heart Failure. PLoS One 6, e27901 (2011).
    1. Lopez B. et al. Usefulness of serum carboxy-terminal propeptide of procollagen type I in assessment of the cardioreparative ability of antihypertensive treatment in hypertensive patients. Circulation 104, 286–291 (2001).
    1. Wynn T. A. Cellular and molecular mechanisms of fibrosis. The Journal of pathology 214, 199–210, doi: 10.1002/path.2277 (2008).

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