Mesenchymal stem cells suppress cardiac alternans by activation of PI3K mediated nitroso-redox pathway. (September 2016)

• Record Type: Journal Article
• Authors: Sattayaprasert, Prasongchai; Nassal, Drew M.; Wan, Xiaoping; Deschenes, Isabelle; Laurita, Kenneth R.
• Is Part Of: Journal of molecular and cellular cardiology. Volume 98(2016:Sep.)
• Page Start: 138
• Page End: 145
• Publication Date: 2016-09
• Subjects: Mesenchymal stem cells -- Alternans -- Oxidative stress -- Arrhythmia -- SERCA2a; Cardiology -- Periodicals; Heart Diseases -- Periodicals; Molecular Biology -- Periodicals; Cardiologie -- Périodiques; Cardiology; Electronic journals; Periodicals; 616.12
• DOI: 10.1016/j.yjmcc.2016.05.014
• Languages: English
• ISSNs: 0022-2828

Abstract

Abstract: Background: 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. Methods and results: 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 200 μM H2 O2 . 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 20 μM 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. Conclusion: 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. Highlights: Human mesenchymal stem cells suppress cardiac alternans measured in human cardiac myocytes in the setting of oxidative stress. Suppression of cardiac alternans by mesenchymal stem cells is, largely, paracrine in nature. The mechanism of cardiac alternans suppression by mesenchymal stem cells is activation of a PI3K-mediated nitroso-redox pathway that improves Ca ++ cycling.