title: Mesenchymal stem cells suppress cardiac alternans by activation of PI3K mediated nitroso-redox pathway.
abstract: The paracrine action of non-cardiac progenitor cells is robust, but not well understood. Mesenchymal stem cells (MSC) have been shown to enhance calcium (Ca(++)) cycling in myocytes. Therefore, we hypothesized that MSCs can suppress cardiac alternans, an important arrhythmia substrate, by paracrine action on Ca(++) cycling.
  
  
  
  Human cardiac myocyte monolayers derived from iPS cells (hCM) were cultured without or with human MSCs (hMSC) directly or plated on a transwell insert. Ca(++) transient alternans (Ca(++) ALT) and Ca(++) transient duration (CaD) were measured from hCM monolayers following application of 200μM H2O2. Ca(++) ALT in hCM was significantly decreased when cultured with hMSCs directly (97%, p<0.0001) and when cultured with hMSC in the transwell insert (80%, p<0.0001). When hCM with hMSCs were pretreated with PI3K or eNOS inhibitors, Ca(++) ALT was larger than baseline by 20% (p<0.0001) and 36% (p<0.0001), respectively. In contrast, Ca(++) ALT was reduced by 89% compared to baseline (p<0.0001) when hCM monolayers without hMSCs were pretreated with 20μM GSNO. In all experiments, changes in Ca(++) ALT were mirrored by changes in CaD. Finally, real time quantitative PCR revealed no significant differences in mRNA expression of RyR2, SERCA2a, and phospholamban between hCM cultured with or without hMSCs.
  
  
  
  Ca(++) ALT is suppressed by hMSCs in a paracrine fashion due to activation of a PI3K-mediated nitroso-redox pathway. These findings demonstrate, for the first time, how stem cell therapy might be antiarrhythmic by suppressing cardiac alternans through paracrine action on Ca(++) cycling.
authors.affiliation: Department of Internal Medicine, MetroHealth Campus of Case Western Reserve University, Cleveland, OH, United States; Heart & Vascular Research Center, MetroHealth Campus of Case Western Reserve University, Cleveland, OH, United States.
authors.forename: Prasongchai
authors.initials: P
authors.lastname: Sattayaprasert
authors.affiliation: Heart & Vascular Research Center, MetroHealth Campus of Case Western Reserve University, Cleveland, OH, United States.
authors.forename: Drew M
authors.initials: DM
authors.lastname: Nassal
authors.affiliation: Heart & Vascular Research Center, MetroHealth Campus of Case Western Reserve University, Cleveland, OH, United States.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Wan
authors.affiliation: Heart & Vascular Research Center, MetroHealth Campus of Case Western Reserve University, Cleveland, OH, United States.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Deschenes
authors.affiliation: Heart & Vascular Research Center, MetroHealth Campus of Case Western Reserve University, Cleveland, OH, United States. Electronic address: Kenneth.Laurita@case.edu.
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: Laurita
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling; D002450:Cell Communication; D015870:Gene Expression; D005936:Glucans / Q000378:metabolism*; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism*; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D005936:Glucans; D019837:Ryanodine Receptor Calcium Release Channel; C439358:alternan; D006861:Hydrogen Peroxide; D019869:Phosphatidylinositol 3-Kinases; D002118:Calcium
keywords: Alternans; Arrhythmia; Mesenchymal stem cells; Oxidative stress; SERCA2a