Biochemical and Biophysical Research Communications
Chronic angiotensin-(1–7) administration improves vascular remodeling after angioplasty through the regulation of the TGF-β/Smad signaling pathway in rabbits☆
Introduction
Coronary reperfusion treatment is widely used to restore blood flow to the ischemic myocardium. Vascular remodeling has been identified as the major cause for the delayed failure of angioplasty procedures [1]. Vascular remodeling may result from abnormal wound healing, including initial constriction, neointimal formation, and extracellular matrix (ECM) accumulation [2]. Experiments in humans and animal models have indicated that the renin-angiotensin system (RAS) plays a very important role in vascular remodeling [3]. RAS intervention, through Angiotensin converting enzyme inhibitors (ACE-I) and angiotensin receptor antagonist (ARB), has been proven to be a rather safe and effective method for the treatment of cardiovascular diseases [4], [5]. Therefore, targeting the RAS-axis may provide more potent therapies for the inhibition of vascular remodeling after angioplasty.
Angiotensin-(1–7) [ANG-(1–7)] is an endogenous bioactive peptide in the RAS. It is considered to have a counteracting effect to angiotensin II (ANG II) on the cardiovascular system by its inhibition of cell migration and proliferation, ECM deposition, inflammation, thrombosis [6]. Most effects are beneficial to the prevention of vascular remodeling. Furthermore, Langeveld et al. [7] and Strawn et al. [8] demonstrated that continuous ANG-(1–7) infusion attenuates neointimal formation after vascular injury and reduced in-stent restenosis (ISR) in a rat model, respectively. No further investigation has been undertaken to observe effects of ANG-(1–7) on collagen synthesis, which is another important aspect that affects vascular remodeling after angioplasty. In addition, the mechanism by which ANG-(1–7) prevents remodeling after vascular injury has not yet been studied in detail. Over the past few years, there has been an increased focus on the mechanism for the anti-remodeling action of ANG-(1–7) in heart. Iwata et al. [9] demonstrated that ANG-(1–7) could decrease transforming growth factor-beta 1 (TGF-β1) mRNA levels in cultured adult rat cardiac fibroblasts (ARCF). Grobe et al. [10] recently demonstrated that the plasma levels of TGF-β1 in myocardial infarction rat models were 40% lower in the group with ANGII co-infused with ANG-(1–7) than in the group with ANGII alone. Taken together, these observations reveal a trend towards a suppression in the expression levels of TGF-β1 by ANG-(1–7) during the remodeling phase in heart, which suggests a possible mechanism for the anti-remodeling activity of ANG-(1–7). The vascular response to angioplasty and the response of the myocardium to infarction are very similar, with an early accumulation of myofibroblasts and a subsequent loss of cells that results in an acellular matrix-rich structure. Given this similarity, we hypothesized that the anti-remodeling action of ANG-(1–7) during vascular remodeling after angioplasty may be associated with the TGF-β1 signaling pathway.
TGF-β belongs to a superfamily of proteins that serve critical roles in ECM production and the regulation of cell growth, differentiation, migration, and apoptosis in different organ systems. TGF-β1, which is the most important isoform for the cardiovascular systemhas been reported to be a most potent profibrotic cytokine [11]. Moreover, many studies [12] found that TGF-β expression is increased in human restenotic lesions as well as in neointimal hyperplasia after balloon injury in animals. In experimental models [13], [14], [15], targeting TGF-β by antibody, soluble receptor or ribozyme oligonucleotides effectively reduced neointimal formation and the constrictive remodeling that are associated with angioplasty. The mechanisms involved in TGF-β-mediated vascular remodeling are complex, including the activation of Smad protein, protein kinases-production of mediators [16].
In the present study, ANG-(1–7) was given for 4 weeks to a rabbit abdominal aorta injury model to explore the effects of chronic ANG-(1–7) administration on vascular remodeling after angioplasty. Furthermore, the anti-remodeling response to ANG-(1–7) was characterized by examining collagen synthesis and the expression levels of the protein components of the TGF-β signaling pathway, including those in the Smad-dependent (Smad2) and Smad-independent (p38) pathway. The resulting data allowed us to determine that the mechanism of the anti-remodeling activity of ANG-(1–7) after angioplasty may depend on the inhibition of the TGF-β/Smad signaling pathway and ECM deposition.
Section snippets
Materials and methods
Animals. The experimental population consists 32 healthy, 12-week-old New Zealand white rabbits weighing 1.7–2.2 kg, which were derived from the Animal Experiment Centre of Guangdong Province, China and were raised in the Department of Animal Experiment Center of Sun Yat-sen University. All animals were provided with normal rabbit chow and tap water and housed in individual cages with a 12-dark/light cycle. All animal experimental procedures had ethical approval and followed the Guidelines for
Effects of chronic treatment with ANG-(1–7) on blood pressure and heart rate
Chronic ANG-(1–7) injection had no effect on BP or HR in rabbits after balloon injury. The systolic BP (SBP), diastolic BP (DBP) and HR (96 ± 9 mm Hg, 63 ± 7 mm Hg, and 343 ± 35 bpm, respectively, n = 8) in the ANG-(1–7) group rabbits were not different from those of the control group (93 ± 13 mm Hg, 62 ± 8 mm Hg, and 370 ± 29 bpm, respectively, n = 8) (Supplement 2).
Angiography result and effects of ANG-(1–7) on neointimal formation
After the intravenous infusion of ANG-(1–7) for four weeks, the vascular wall in the ANG-(1–7) group was smoother than that of the control group, as seen
Discussion
Following a four-week intravenous infusion ANG-(1–7) effectively reduced neointimal growth after angioplasty in a rabbit model. The abdominal angiography showed that the residual lumen was better preserved in the ANG-(1–7) group than in the control group. Furthermore, the HE and Weigert stains showed that ANG-(1–7) significantly reduced the neointimal thickness, neointimal area and restenosis rates when compared with those of the control group. The specific antagonist for ANG-(1–7), A-779,
Conclusion
In summary, this study is the first to our knowledge that provides evidence that ANG-(1–7) reduces vascular remodeling, by not only inhibiting neointimal formation but also decreasing collagen secretion. These effects are possibly mediated through the regulation of the TGF-β/Smad signaling pathway in an in vivo, rabbit abdominal aorta injury model. These findings may lead to a new therapy for diseases that involve vascular remodeling in the presence or absence of injury.
Acknowledgments
We thank Mr. Gang Dai and Dr. Ren Li for their technical assistance.
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This study was financially supported by the Science and Technology Program of Guangdong Province [Grant 2005B10401020].