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In Vitro Study of the Effect of Nifedipine on Human Fibroblasts

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In Vitro Study of the Effect of Nifedipine on Human Fibroblasts applied sciences Article Biology of Drug-Induced Gingival Hyperplasia: In Vitro Study of the Effect of Nifedipine on Human Fibroblasts Dorina Lauritano 1,*,† , Giulia Moreo 1,†, Fedora Della Vella 2 , Annalisa Palmieri 3, Francesco Carinci 4 and Massimo Petruzzi 2 1 Centre of Neuroscience of Milan, Department of Medicine and Surgery, University of Milano-Bicocca, 20126 Milan, Italy; [email protected] 2 Interdisciplinary Department of Medicine, University of Bari, 70121 Bari, Italy; [email protected] (F.D.V.); [email protected] (M.P.) 3 Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Via Belmoro 8, 40126 Bologna, Italy; [email protected] 4 Department of Translational Medicine, University of Ferrara, 44121 Ferrara, Italy; [email protected] * Correspondence: [email protected] † These authors contribute equally to this work. Abstract: Background: It has been proven that the antihypertensive agent nifedipine can cause gingi- val overgrowth as a side effect. The aim of this study was to analyze the effects of pharmacological treatment with nifedipine on human gingival fibroblasts activity, investigating the possible patho- genetic mechanisms that lead to the onset of gingival enlargement. Methods: The expression profile of 57 genes belonging to the “Extracellular Matrix and Adhesion Molecules” pathway, fibroblasts’ viability at different drug concentrations, and E-cadherin levels in treated fibroblasts were assessed using real-time Polymerase Chain Reaction, PrestoBlue™ cell viability test, and an enzyme-linked immunoassay (ELISA), respectively. Results: Metalloproteinase 24 and 8 (MMP24, MMP8) showed Citation: Lauritano, D.; Moreo, G.; significant upregulation in treated cells with respect to the control group, and cell adhesion gene Vella, F.D.; Palmieri, A.; Carinci, F.; CDH1 (E-cadherin) levels were recorded as increased in treated fibroblasts using both real-time Petruzzi, M. Biology of Drug-Induced PCR and ELISA. Downregulation was observed for transmembrane receptors ITGA6 and ITGB4, Gingival Hyperplasia: In Vitro Study the basement membrane constituent LAMA1 and LAMB1, and the extracellular matrix protease of the Effect of Nifedipine on Human MMP11, MMP16, and MMP26. Conclusions: The obtained data suggested that the pathogenesis of Fibroblasts. Appl. Sci. 2021, 11, 3287. https://doi.org/10.3390/app11073287 nifedipine-induced gingival overgrowth is characterized by an excessive accumulation of collagen due to the inhibition of collagen intracellular and extracellular degradation pathways. Academic Editor: Francesca Zara Keywords: drug-induced gingival overgrowth; nifedipine; human gingival fibroblasts; hypertension Received: 23 February 2021 therapy side effects Accepted: 1 April 2021 Published: 6 April 2021 Publisher’s Note: MDPI stays neutral 1. Introduction with regard to jurisdictional claims in The most frequent risk factor for myocardial infarction, congestive heart failure, published maps and institutional affil- and stroke is hypertension [1,2]. Nifedipine is used as an antihypertensive and antiang- iations. inal agent, providing vascular smooth muscle relaxation and negative ionotropic and chronotropic effects on. This drug is able to inhibit voltage-dependent L-type calcium channels in vascular smooth muscles and myocardial cells, preventing the entry of cal- cium ions. The reduction of intracellular calcium level causes a decrease of peripheral Copyright: © 2021 by the authors. arterial vascular resistance and the dilatation of coronary arteries. These conditions result Licensee MDPI, Basel, Switzerland. in systemic blood pressure reduction and in myocardial oxygen delivery increase [3–6]. This article is an open access article The systematic review and meta-analysis by Ross et al. [7] analyzed the side effects of distributed under the terms and antihypertensive agents on 28,922 patients, reporting that calcium channel blockers are conditions of the Creative Commons most associated with neurologic (17.6%), cardiovascular (11.9%), respiratory (7.8%), and Attribution (CC BY) license (https:// dermatologic (6.8%) adverse events. The literature also proved gingival overgrowth (GO) creativecommons.org/licenses/by/ to be a further side effect associated with the administration of calcium channel blockers, 4.0/). Appl. Sci. 2021, 11, 3287. https://doi.org/10.3390/app11073287 https://www.mdpi.com/journal/applsci Appl. Sci. 2021, 11, 3287 2 of 10 including nifedipine. The cross-sectional study by Miranda et al. [8] recorded a significantly higher prevalence of gingival enlargement in 65 patients treated with nifedipine compared with the control group, and it also assessed, in line with other studies, that gingival lesions were more severe in the vestibular area of inferior and anterior teeth [9,10]. The onset of gingival overgrowth is not only associated with antihypertensive therapy, but also with anticonvulsant and immunosuppressant drugs’ chronic administration: the prevalence of drug-induced gingival enlargement (DIGO) was demonstrated to be around 50–70%, 30%, and 25–30% in the case of phenytoin [11,12], nifedipine [8], and cyclosporine, respectively [12]. Clinical manifestation of GO is similar for all the cited drugs: it usually manifests itself during the first 3 months of the therapy, reaching its widest expression after 9–12 months [13]. The study of 2012 by Miranda et al. [14] described the manifestation of gingival lesions, evaluating two clinical indices, i.e., vertical and horizontal overgrowth: GO occurs at first in the area of interdental papilla, as localized nodullary enlargement (horizontal growth), and it afterwards expands to the dental crown (vertical growth), interfering with mastication. The severity of drug-induced gingival enlargement (DIGO) seems to be influenced by plaque scores and gingival inflammation [15]. In particular, with reference to nifedipine, some studies demonstrated that the onset and the development of GO depends on high plaque index, administration of high drug doses, and genetic factors [16,17]. Moreover, Trackman et al. assessed that the characteristics of GO induced by nifedipine, phenytoin, and ciclosporin are different: gingival lesions associated with anticonvulsants are the most fibrotic, gingival tissue in patients treated with cyclosporin appears highly inflamed, while lesions related to nifedipine administration have intermediate characteristics [18]. The increase of the volume of gingival tissues represents the consequence of the connective tissue response: the alterations in cellular and extracellular matrix (ECM) metabolisms leads to an excessive storage of extracellular matrix proteins (collagens or amorphous ground substance) [15,19]. Calcium channel blockers can inhibit the intracel- lular calcium uptake, an event that leads to the stimulation of gingival fibroblasts, which are mainly involved in the synthesis and enzymatic degradation of ECM proteins. The pathogenetic hypothesis of DIGO is based on the presence of genetically predisposed gingival fibroblasts, which produce enormous quantity of collagen, consequently causing a disproportion in the collagen synthesis-degradation mechanism [13,20]. Some authors demonstrated otherwise that the storage of collagen in DIGO is the result of the inhibition of the collagen degradation process [21]. Objectives This study aimed to analyze the effects of pharmacological treatment with nifedipine on human gingival fibroblasts’ activity, investigating the possible pathogenetic mechanisms that lead to the onset of gingival enlargement. The expression profile of 57 genes belonging to the “Extracellular Matrix and Adhesion Molecules” pathway, fibroblasts’ viability at different drug concentrations, and E-cadherin levels in treated fibroblasts were assessed. 2. Materials and Methods 2.1. Primary Human Fibroblast Cells’ Culture Human gingival fibroblasts were purchased from ATCC® Cell Lines. Cells at the second passage were cultured in Dulbecco’s Modified Eagle Medium (DMEM) (Sigma Aldrich, Inc., St. Louis, MO, USA) supplemented with 10% fetal calf serum and antibiotics (penicillin 100 U/mL and streptomycin 100 micrograms/mL, Sigma Aldrich, Inc., St. Louis, MO, USA). Cells were replicated for subsequent experiments. 2.2. Cell Viability Test Human gingival fibroblasts were seeded into 96-well plates at a density of 104 cells per well containing 100 µL of cell culture medium and incubated for 24 h to allow cell adherence. Appl. Sci. 2021, 11, 3287 3 of 10 A stock solution of nifedipine (Nifedicor, Meda Pharma Spa, Mylan, Italy) was pre- pared dissolving 1 mg of nifedipine powder in 1 mL of absolute ethanol. The stock solution of Nnifedipine (1 mg/mL) was dissolved in DMEM medium to prepare serial dilution at the concentrations of 5000, 2000, 1000, 500, and 100 ng/mL. The vehicle absolute ethanol dissolved in the cell culture medium at the same concen- tration used to prepare the serial dilutions was used as a negative control. After 24 h of incubation, cell viability was measured using PrestoBlue™ Reagent Protocol (Invitrogen, Carlsbad, CA, USA) according to the manufacturer’s instructions, as previously described [22]. 2.3. Cell Treatment Once semi-confluence was reached (about 70% of confluence), cells were detached from flasks by trypsin-ethylenediaminetetraacetic acid (EDTA) and seeded at a density of 1 × 105 cells/mL into 9 cm2 (3 mL) wells. Cells were washed two times with phosphate- buffered saline (PBS) and incubated for 16 h at 37 ◦C with serum-free DMEM. After
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