title: Acute pergolide exposure stiffens engineered valve interstitial cell tissues and reduces contractility in vitro.
abstract: Medications based on ergoline-derived dopamine and serotonin agonists are associated with off-target toxicities that include valvular heart disease (VHD). Reports of drug-induced VHD resulted in the withdrawal of appetite suppressants containing fenfluramine and phentermine from the US market in 1997 and pergolide, a Parkinson's disease medication, in 2007. Recent evidence suggests that serotonin receptor activity affected by these medications modulates cardiac valve interstitial cell activation and subsequent valvular remodeling, which can lead to cardiac valve fibrosis and dysfunction similar to that seen in carcinoid heart disease. Failure to identify these risks prior to market and continued use of similar drugs reaffirm the need to improve preclinical evaluation of drug-induced VHD. Here, we present two complimentary assays to measure stiffness and contractile stresses generated by engineered valvular tissues in vitro. As a case study, we measured the effects of acute (24 h) pergolide exposure to engineered porcine aortic valve interstitial cell (AVIC) tissues. Pergolide exposure led to increased tissue stiffness, but it decreased both basal and active contractile tone stresses generated by AVIC tissues. Pergolide exposure also disrupted AVIC tissue organization (i.e., tissue anisotropy), suggesting that the mechanical properties and contractile functionality of these tissues are governed by their ability to maintain their structure. We expect further use of these assays to identify off-target drug effects that alter the phenotypic balance of AVICs, disrupt their ability to maintain mechanical homeostasis, and lead to VHD.
authors.affiliation: Disease Biophysics Group, Wyss Institute for Biologically Inspired Engineering, John A. Paulson School of Engineering and Applied Sciences, Harvard University, 29 Oxford St, Pierce Hall 321, Cambridge, MA 02138, USA.
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Capulli
authors.affiliation: Disease Biophysics Group, Wyss Institute for Biologically Inspired Engineering, John A. Paulson School of Engineering and Applied Sciences, Harvard University, 29 Oxford St, Pierce Hall 321, Cambridge, MA 02138, USA.
authors.forename: Luke A
authors.initials: LA
authors.lastname: MacQueen
authors.affiliation: Disease Biophysics Group, Wyss Institute for Biologically Inspired Engineering, John A. Paulson School of Engineering and Applied Sciences, Harvard University, 29 Oxford St, Pierce Hall 321, Cambridge, MA 02138, USA.
authors.forename: Blakely B
authors.initials: BB
authors.lastname: O'Connor
authors.affiliation: Disease Biophysics Group, Wyss Institute for Biologically Inspired Engineering, John A. Paulson School of Engineering and Applied Sciences, Harvard University, 29 Oxford St, Pierce Hall 321, Cambridge, MA 02138, USA.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Dauth
authors.affiliation: Disease Biophysics Group, Wyss Institute for Biologically Inspired Engineering, John A. Paulson School of Engineering and Applied Sciences, Harvard University, 29 Oxford St, Pierce Hall 321, Cambridge, MA 02138, USA. Electronic address: kkparker@seas.harvard.edu.
authors.forename: Kevin Kit
authors.initials: KK
authors.lastname: Parker
mesh_terms: D000818:Animals; D001021:Aortic Valve / Q000187:drug effects*; D015153:Blotting, Western; D018491:Dopamine Agonists / Q000633:toxicity*; D004353:Drug Evaluation, Preclinical; D005109:Extracellular Matrix / Q000187:drug effects / Q000473:pathology; D005347:Fibroblasts / Q000187:drug effects / Q000473:pathology; D066298:In Vitro Techniques / Q000379:methods*; D009119:Muscle Contraction / Q000187:drug effects; D010479:Pergolide / Q000633:toxicity*; D013552:Swine; D023822:Tissue Engineering / Q000379:methods; D059289:Vascular Stiffness
chemical_list: D018491:Dopamine Agonists; D010479:Pergolide
keywords: Ergoline; Pergolide; Serotonin agonist; Valve interstitial cells; Valvular heart disease