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Curcumin Enhances Vascular Contractility Via Induction of Myocardin in Mouse Smooth Muscle Cells

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Curcumin Enhances Vascular Contractility Via Induction of Myocardin in Mouse Smooth Muscle Cells Acta Pharmacologica Sinica 2017: 1329–1339 © 2017 CPS and SIMM All rights reserved 1671-4083/17 www.nature.com/aps Original Article Curcumin enhances vascular contractility via induction of myocardin in mouse smooth muscle cells Shao-wei SUN1, Wen-juan TONG2, Zi-fen GUO1, Qin-hui TUO3, Xiao-yong LEI1, Cai-ping ZHANG1, Duan-fang LIAO3, *, Jian- xiong CHEN3, 4 1Institute of Pharmacy and Pharmacology, School of Life Science and Technology, University of South China, Hengyang 421001, China; 2Department of Gynecology and Obstetrics, First Affiliated Hospital, University of South China, Hengyang 421001, China; 3Medical School, Hunan University of Chinese Medicine, Changsha 410208, China; 4Department of Pharmacology and Toxicology, University of Mississippi Medical Center, School of Medicine, Jackson, MS, USA Abstract A variety of cardiovascular diseases is accompanied by the loss of vascular contractility. This study sought to investigate the effects of curcumin, a natural polyphenolic compound present in turmeric, on mouse vascular contractility and the underlying mechanisms. After mice were administered curcumin (100 mg·kg-1·d-1, ig) for 6 weeks, the contractile responses of the thoracic aorta to KCl and phenylephrine were significantly enhanced compared with the control group. Furthermore, the contractility of vascular smooth muscle (SM) was significantly enhanced after incubation in curcumin (25 µmol/L) for 4 d, which was accompanied by upregulated expression of SM marker contractile proteins SM22α and SM α-actin. In cultured vascular smooth muscle cells (VSMCs), curcumin (10, 25, 50 µmol/L) significantly increased the expression of myocardin, a “master regulator” of SM gene expression. Curcumin treatment also significantly increased the levels of caveolin-1 in VSMCs. We found that as a result of the upregulation of caveolin-1, curcumin blocked the activation of Notch1 and thereby abolished Notch1-inhibited myocardin expression. Knockdown of caveolin-1 or activation of Notch1 signaling with Jagged1 (2 µg/mL) diminished these effects of curcumin in VSMCs. These findings suggest that curcumin induces the expression of myocardin in mouse smooth muscle cells via a variety of mechanisms, including caveolin-1-mediated inhibition of Notch1 activation and Notch1-mediated repression of myocardin expression. This may represent a novel pathway, through which curcumin protects blood vessels via the beneficial regulation of SM contractility. Keywords: curcumin; smooth muscle; vascular contractility; myocardin; caveolin-1; Notch1 Acta Pharmacologica Sinica (2017) 38: 1329–1339; doi: 10.1038/aps.2017.18; published online 1 May 2017 Introduction rosis. The underlying pathophysiology of vascular dysfunc- Blood vessels, which are part of the circulatory system, are tion occurs in numerous forms and often involves vascular responsible for the transport of blood and delivery of essen- SM losing its contractile characteristics[1-3]. Recent studies also tial nutrients to downstream tissues. The primary structural, point to dysfunctional vascular SM as an underlying factor of muscular, and functional unit of a blood vessel is the medial cardiovascular disease, such as atherosclerosis and vascular wall, which is composed primarily of vascular smooth muscle aging[4, 5]. Logically, therapeutically targeting vascular SM (SM). Vascular SM provides a critical regulatory role in ves- for further discovery and potential therapeutic utility against sel relaxation and contraction to ensure adequate tissue blood cardiovascular disease is highly significant and essential. flow and to maintain proper localized arterial blood pressures Vascular smooth muscle cells (VSMCs) are highly specialized and perfusion of downstream tissues. Vascular dysfunction cells that constitute basic structural and functional elements is the root cause of a variety of important disease processes, of vascular SM. By contracting and relaxing, they regulate including hypertension, myocardial infarction, and atheroscle- lumen caliber and thus arterial and venous tone and vascular resistance, which enables vascular SM to control the distribu- *To whom correspondence should be addressed. tion of blood flow throughout the body. However, VSMCs E-mail [email protected] are also thought to play a major role in vascular dysfunction Received 2017-01-14 Accepted 2017-02-20 in a variety of disease states[6, 7]. Mature VSMCs are normally www.nature.com/aps 1330 Sun SW et al highly differentiated and characterized by the expression of a secondary antibodies were obtained from Santa Cruz Biotech- range of SM-specific contractile proteins, including SM α-actin, nology (Santa Cruz, USA). SM22α, and h1-calponin[8, 9]. A number of works have shown that the transcription of these muscle genes and almost all SM Animals genes were regulated by myocardin[10]. Myocardin is a master C57BL/6 male mice, 6–8 weeks of age, were purchased from regulator of VSMC differentiation that is found only in smooth Jingda Laboratory Animal Technology Co Ltd (Changsha, and cardiac muscle and regulates gene expression by forming China). Male homozygous caveolin-1 knockout (caveolin-1 a higher order complex with serum response factor (SRF)[11]. KO) mice with a C57BL/6 genetic background were pur- Critical roles of myocardin in SM have been revealed in mice chased from the Jackson Laboratory (Stock No: 007083). All with global or conditional knockout of the myocardin gene. mice were acclimatized with 12 h dark-light cycles under a Mice with homozygous null mutations for myocardin die constant temperature (22±2 °C) and had free access to water during early aortic development, and embryos fail to express and food. All experiments were carried out in accordance SMC markers[12]. Mice with myocardin conditional mutations with the internationally accepted guide for the care and use of in SMCs also died at six months and exhibited deformation of laboratory animals and were approved by the Animal Ethics the structure of the great arteries, along with increased dilation Committee of Hunan University of Chinese Medicine. One set of the stomach, small intestine, bladder and ureters[13]. Forced of mice was fed with curcumin. The curcumin was dissolved expression of myocardin increases smooth muscle contractile in ethanol and administered to the mice via gavages of 100 proteins and contributes to the development of SM contractil- mg/kg body weight/day for 6 weeks. An equivalent amount ity[14]. Thus, myocardin could be a prime target for regulation of ethanol was used for the control group. of vascular contractility. Curcumin is a natural polyphenolic compound present Cells in turmeric and one of the most extensively studied natural Human VSMCs were purchased from Cell Bank of Chinese products. Curcumin exerts a wide range of bioactivities impli- Academy of Sciences in Shanghai. Cells were grown in high cated in anti-oxidant, anti-inflammatory, anti-carcinogenic glucose DMEM medium with supplements (10% FBS, 100 and wound-healing effects[15-19]. It is renowned for its medical U/mL penicillin G, 100 µg/mL streptomycin, and 2 mmol/L properties and as a cure for several types of diseases, including glutamine). According to the IC50 value of VSMCs determined diabetes, cancers and cardiovascular diseases. Mounting evi- previously by us, curcumin was applied at an end concentra- dence suggests that curcumin has vascular protective effects tion of 10–50 μmol/L for all assays. For controls, the carrier in cardiovascular disease[20, 21]. Our study found that curcumin (DMSO) diluted accordingly to the curcumin working solu- increased vascular contractility in C57BL/6 mice. However, tions was applied to the cells. it remains unknown whether curcumin enhances contractility of blood vessels via upregulation of myocardin and its target RNA interference studies genes. To test the hypothesis that curcumin improves vascu- RNA interference was based on the pGreenPuro system (Add- lar SM function via the induction of myocardin, we examined gene, USA) expressing small-hairpin RNA (shRNA). pGreen- myocardin expression in vascular tissues from mice treated puro-caveolin-1-shRNA and pGreenPuro-vector constructs, with curcumin and their contractility in vitro. The underlying encoding shRNA for caveolin-1 or a negative control (vector), mechanisms were further investigated using cultured VSMCs. were prepared by inserting the target sequence into pGreen- Puro. The shRNA oligonucleotide was designed with 19 bases Materials and methods in the sense strand (5’-ACCAGAAGGGACACACAGT-3’) Reagents and antibodies and the antisense strand (5’-ACTGTGTGTCCCTTCTGGT-3’), Fetal bovine serum (FBS) and Dulbecco’s minimum essential which targeted region nt 424–442 of the caveolin-1 coding medium (DMEM) were purchased from Gibco (Grand Island, sequence, separated by a hairpin loop (TTCAAGAGA). The USA). KCl and phenylephrine (PE) were purchased from ligation products were transformed into E coli, clones with Sigma Aldrich (Sigma-Aldrich, USA). Jagged1 recombinant the shRNA insert were selected and amplified, the plasmid human protein was purchased from Thermo Fisher Scientific DNA was isolated, and selected reconstructed plasmids for (Waltham, USA), and Human Caveolin-1 Adenovirus (Ad- transfection were purified with a plasmid purification mini kit Caveolin-1) from Vector BioLabs (Cat. No. 1364). Curcumin (ComWin Biotech Co, Ltd, China). For transfection, VSMCs (purity >98%) was purchased from Sinopharm Chemical were seeded in 6-well plates at 1×106 cells/well and allowed Reagent
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