title: An In Vitro Cynomolgus Vascular Surrogate System for Preclinical Drug Assessment and Human Translation.
abstract: OBJECTIVE
  The predictive value of animal and in vitro systems for drug development is limited, particularly for nonhuman primate studies as it is difficult to deduce the drug mechanism of action. We describe the development of an in vitro cynomolgus macaque vascular system that reflects the in vivo biology of healthy, atheroprone, or advanced inflammatory cardiovascular disease conditions.
  
  
  RESULTS
  We compare the responses of the in vitro human and cynomolgus vascular systems to 4 statins. Although statins exert beneficial pleiotropic effects on the human vasculature, the mechanism of action is difficult to investigate at the tissue level. Using RNA sequencing, we quantified the response to statins and report that most statins significantly increased the expression of genes that promote vascular health while suppressing inflammatory cytokine gene expression. Applying computational pathway analytics, we identified statin-regulated biological themes, independent of cholesterol lowering, that provide mechanisms for off-target effects, including thrombosis, cell cycle regulation, glycogen metabolism, and ethanol degradation.
  
  
  CONCLUSIONS
  The cynomolgus vascular system described herein mimics the baseline and inflammatory regional biology of the human vasculature, including statin responsiveness, and provides mechanistic insight not achievable in vivo.
authors: From the NASH Program (B.K.C., R.F.), Technology and Research Platforms (M.B.S.), Rare Diseases Program (M.S.C.), Vascular Program (E.B., D.M.), Pharmacology (R.A.F.), Cell Culture (A.W.P.), Computational Biology (M.L., A.M.), VP of Research and Development (B.R.W.), and Chief Scientific Officer (B.R.B.), HemoShear Therapeutics LLC, Charlottesville, VA (B.K.C., M.B.S., R.F., M.S.C., E.B., R.A.F., A.W.P., M.L., A.M., D.M., B.R.W, B.R.B.); and Comparative Biology and Safety Sciences (C.W.Q., J.R.T.), Amgen Inc, Thousand Oaks, CA (C.W.Q., J.R.T.).
authors: Banumathi K
authors: BK
authors: Cole
authors: From the NASH Program (B.K.C., R.F.), Technology and Research Platforms (M.B.S.), Rare Diseases Program (M.S.C.), Vascular Program (E.B., D.M.), Pharmacology (R.A.F.), Cell Culture (A.W.P.), Computational Biology (M.L., A.M.), VP of Research and Development (B.R.W.), and Chief Scientific Officer (B.R.B.), HemoShear Therapeutics LLC, Charlottesville, VA (B.K.C., M.B.S., R.F., M.S.C., E.B., R.A.F., A.W.P., M.L., A.M., D.M., B.R.W, B.R.B.); and Comparative Biology and Safety Sciences (C.W.Q., J.R.T.), Amgen Inc, Thousand Oaks, CA (C.W.Q., J.R.T.).
authors: Michael B
authors: MB
authors: Simmers
authors: From the NASH Program (B.K.C., R.F.), Technology and Research Platforms (M.B.S.), Rare Diseases Program (M.S.C.), Vascular Program (E.B., D.M.), Pharmacology (R.A.F.), Cell Culture (A.W.P.), Computational Biology (M.L., A.M.), VP of Research and Development (B.R.W.), and Chief Scientific Officer (B.R.B.), HemoShear Therapeutics LLC, Charlottesville, VA (B.K.C., M.B.S., R.F., M.S.C., E.B., R.A.F., A.W.P., M.L., A.M., D.M., B.R.W, B.R.B.); and Comparative Biology and Safety Sciences (C.W.Q., J.R.T.), Amgen Inc, Thousand Oaks, CA (C.W.Q., J.R.T.).
authors: Ryan
authors: R
authors: Feaver
authors: From the NASH Program (B.K.C., R.F.), Technology and Research Platforms (M.B.S.), Rare Diseases Program (M.S.C.), Vascular Program (E.B., D.M.), Pharmacology (R.A.F.), Cell Culture (A.W.P.), Computational Biology (M.L., A.M.), VP of Research and Development (B.R.W.), and Chief Scientific Officer (B.R.B.), HemoShear Therapeutics LLC, Charlottesville, VA (B.K.C., M.B.S., R.F., M.S.C., E.B., R.A.F., A.W.P., M.L., A.M., D.M., B.R.W, B.R.B.); and Comparative Biology and Safety Sciences (C.W.Q., J.R.T.), Amgen Inc, Thousand Oaks, CA (C.W.Q., J.R.T.).
authors: Charles W
authors: CW
authors: Qualls
authors: From the NASH Program (B.K.C., R.F.), Technology and Research Platforms (M.B.S.), Rare Diseases Program (M.S.C.), Vascular Program (E.B., D.M.), Pharmacology (R.A.F.), Cell Culture (A.W.P.), Computational Biology (M.L., A.M.), VP of Research and Development (B.R.W.), and Chief Scientific Officer (B.R.B.), HemoShear Therapeutics LLC, Charlottesville, VA (B.K.C., M.B.S., R.F., M.S.C., E.B., R.A.F., A.W.P., M.L., A.M., D.M., B.R.W, B.R.B.); and Comparative Biology and Safety Sciences (C.W.Q., J.R.T.), Amgen Inc, Thousand Oaks, CA (C.W.Q., J.R.T.).
authors: M Sol
authors: MS
authors: Collado
authors: From the NASH Program (B.K.C., R.F.), Technology and Research Platforms (M.B.S.), Rare Diseases Program (M.S.C.), Vascular Program (E.B., D.M.), Pharmacology (R.A.F.), Cell Culture (A.W.P.), Computational Biology (M.L., A.M.), VP of Research and Development (B.R.W.), and Chief Scientific Officer (B.R.B.), HemoShear Therapeutics LLC, Charlottesville, VA (B.K.C., M.B.S., R.F., M.S.C., E.B., R.A.F., A.W.P., M.L., A.M., D.M., B.R.W, B.R.B.); and Comparative Biology and Safety Sciences (C.W.Q., J.R.T.), Amgen Inc, Thousand Oaks, CA (C.W.Q., J.R.T.).
authors: Erica
authors: E
authors: Berzin
authors: From the NASH Program (B.K.C., R.F.), Technology and Research Platforms (M.B.S.), Rare Diseases Program (M.S.C.), Vascular Program (E.B., D.M.), Pharmacology (R.A.F.), Cell Culture (A.W.P.), Computational Biology (M.L., A.M.), VP of Research and Development (B.R.W.), and Chief Scientific Officer (B.R.B.), HemoShear Therapeutics LLC, Charlottesville, VA (B.K.C., M.B.S., R.F., M.S.C., E.B., R.A.F., A.W.P., M.L., A.M., D.M., B.R.W, B.R.B.); and Comparative Biology and Safety Sciences (C.W.Q., J.R.T.), Amgen Inc, Thousand Oaks, CA (C.W.Q., J.R.T.).
authors: Robert A
authors: RA
authors: Figler
authors: From the NASH Program (B.K.C., R.F.), Technology and Research Platforms (M.B.S.), Rare Diseases Program (M.S.C.), Vascular Program (E.B., D.M.), Pharmacology (R.A.F.), Cell Culture (A.W.P.), Computational Biology (M.L., A.M.), VP of Research and Development (B.R.W.), and Chief Scientific Officer (B.R.B.), HemoShear Therapeutics LLC, Charlottesville, VA (B.K.C., M.B.S., R.F., M.S.C., E.B., R.A.F., A.W.P., M.L., A.M., D.M., B.R.W, B.R.B.); and Comparative Biology and Safety Sciences (C.W.Q., J.R.T.), Amgen Inc, Thousand Oaks, CA (C.W.Q., J.R.T.).
authors: Andrew W
authors: AW
authors: Pryor
authors: From the NASH Program (B.K.C., R.F.), Technology and Research Platforms (M.B.S.), Rare Diseases Program (M.S.C.), Vascular Program (E.B., D.M.), Pharmacology (R.A.F.), Cell Culture (A.W.P.), Computational Biology (M.L., A.M.), VP of Research and Development (B.R.W.), and Chief Scientific Officer (B.R.B.), HemoShear Therapeutics LLC, Charlottesville, VA (B.K.C., M.B.S., R.F., M.S.C., E.B., R.A.F., A.W.P., M.L., A.M., D.M., B.R.W, B.R.B.); and Comparative Biology and Safety Sciences (C.W.Q., J.R.T.), Amgen Inc, Thousand Oaks, CA (C.W.Q., J.R.T.).
authors: Mark
authors: M
authors: Lawson
authors: From the NASH Program (B.K.C., R.F.), Technology and Research Platforms (M.B.S.), Rare Diseases Program (M.S.C.), Vascular Program (E.B., D.M.), Pharmacology (R.A.F.), Cell Culture (A.W.P.), Computational Biology (M.L., A.M.), VP of Research and Development (B.R.W.), and Chief Scientific Officer (B.R.B.), HemoShear Therapeutics LLC, Charlottesville, VA (B.K.C., M.B.S., R.F., M.S.C., E.B., R.A.F., A.W.P., M.L., A.M., D.M., B.R.W, B.R.B.); and Comparative Biology and Safety Sciences (C.W.Q., J.R.T.), Amgen Inc, Thousand Oaks, CA (C.W.Q., J.R.T.).
authors: Aaron
authors: A
authors: Mackey
authors: From the NASH Program (B.K.C., R.F.), Technology and Research Platforms (M.B.S.), Rare Diseases Program (M.S.C.), Vascular Program (E.B., D.M.), Pharmacology (R.A.F.), Cell Culture (A.W.P.), Computational Biology (M.L., A.M.), VP of Research and Development (B.R.W.), and Chief Scientific Officer (B.R.B.), HemoShear Therapeutics LLC, Charlottesville, VA (B.K.C., M.B.S., R.F., M.S.C., E.B., R.A.F., A.W.P., M.L., A.M., D.M., B.R.W, B.R.B.); and Comparative Biology and Safety Sciences (C.W.Q., J.R.T.), Amgen Inc, Thousand Oaks, CA (C.W.Q., J.R.T.).
authors: David
authors: D
authors: Manka
authors: From the NASH Program (B.K.C., R.F.), Technology and Research Platforms (M.B.S.), Rare Diseases Program (M.S.C.), Vascular Program (E.B., D.M.), Pharmacology (R.A.F.), Cell Culture (A.W.P.), Computational Biology (M.L., A.M.), VP of Research and Development (B.R.W.), and Chief Scientific Officer (B.R.B.), HemoShear Therapeutics LLC, Charlottesville, VA (B.K.C., M.B.S., R.F., M.S.C., E.B., R.A.F., A.W.P., M.L., A.M., D.M., B.R.W, B.R.B.); and Comparative Biology and Safety Sciences (C.W.Q., J.R.T.), Amgen Inc, Thousand Oaks, CA (C.W.Q., J.R.T.).
authors: Brian R
authors: BR
authors: Wamhoff
authors: From the NASH Program (B.K.C., R.F.), Technology and Research Platforms (M.B.S.), Rare Diseases Program (M.S.C.), Vascular Program (E.B., D.M.), Pharmacology (R.A.F.), Cell Culture (A.W.P.), Computational Biology (M.L., A.M.), VP of Research and Development (B.R.W.), and Chief Scientific Officer (B.R.B.), HemoShear Therapeutics LLC, Charlottesville, VA (B.K.C., M.B.S., R.F., M.S.C., E.B., R.A.F., A.W.P., M.L., A.M., D.M., B.R.W, B.R.B.); and Comparative Biology and Safety Sciences (C.W.Q., J.R.T.), Amgen Inc, Thousand Oaks, CA (C.W.Q., J.R.T.).
authors: James R
authors: JR
authors: Turk
authors: From the NASH Program (B.K.C., R.F.), Technology and Research Platforms (M.B.S.), Rare Diseases Program (M.S.C.), Vascular Program (E.B., D.M.), Pharmacology (R.A.F.), Cell Culture (A.W.P.), Computational Biology (M.L., A.M.), VP of Research and Development (B.R.W.), and Chief Scientific Officer (B.R.B.), HemoShear Therapeutics LLC, Charlottesville, VA (B.K.C., M.B.S., R.F., M.S.C., E.B., R.A.F., A.W.P., M.L., A.M., D.M., B.R.W, B.R.B.); and Comparative Biology and Safety Sciences (C.W.Q., J.R.T.), Amgen Inc, Thousand Oaks, CA (C.W.Q., J.R.T.). Blackman@HemoShear.com.
authors: Brett R
authors: BR
authors: Blackman
mesh_terms: D000818:Animals; D002318:Cardiovascular Diseases / Q000097:blood / Q000188:drug therapy*; D002478:Cells, Cultured; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D042783:Endothelial Cells / Q000187:drug effects; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D066298:In Vitro Techniques; D008077:Lipoproteins, LDL / Q000187:drug effects* / Q000378:metabolism; D008252:Macaca fascicularis; D008955:Models, Cardiovascular; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects; D013045:Species Specificity
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008077:Lipoproteins, LDL
keywords: Macaca fascicularis; cell cycle; hemodynamics; hydroxymethylglutaryl-CoA reductase inhibitors; inflammation