Endocardial TRPC-6 Channels Act as Atrial Mechanosensors and Load-Dependent Modulators of Endocardial/Myocardial Cross-Talk

Vesna Nikolova-Krstevski; Soeren Wagner; Ze Yan Yu; Charles D Cox; Jasmina Cvetkovska; Adam P Hill; Inken G Huttner; Victoria Benson; Andreas A Werdich; Calum MacRae; Michael P Feneley; Oliver Friedrich; Boris Martinac; Diane Fatkin

doi:10.1016/j.jacbts.2017.05.006

Endocardial TRPC-6 Channels Act as Atrial Mechanosensors and Load-Dependent Modulators of Endocardial/Myocardial Cross-Talk

JACC Basic Transl Sci. 2017 Oct 30;2(5):575-590. doi: 10.1016/j.jacbts.2017.05.006. eCollection 2017 Oct.

Authors

Vesna Nikolova-Krstevski^{1

2}, Soeren Wagner³, Ze Yan Yu^{2

4}, Charles D Cox¹, Jasmina Cvetkovska¹, Adam P Hill^{1

2}, Inken G Huttner^{1

2}, Victoria Benson⁵, Andreas A Werdich⁶, Calum MacRae⁶, Michael P Feneley^{2

4

7}, Oliver Friedrich^{1

8}, Boris Martinac^{1

2}, Diane Fatkin^{1

2

7}

Affiliations

¹ Molecular Cardiology and Biophysics Division, Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales, Australia.
² St. Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Kensington, New South Wales, Australia.
³ Department of Anesthesiology, University Clinic Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany.
⁴ Cardiac Physiology and Transplantation Division, Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales, Australia.
⁵ Department of Physiology, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.
⁶ Cardiovascular Division, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
⁷ Cardiology Department, St. Vincent's Hospital, Darlinghurst, New South Wales, Australia.
⁸ Institute of Medical Biotechnology, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany.

Abstract

Mechanoelectrical feedback may increase arrhythmia susceptibility, but the molecular mechanisms are incompletely understood. This study showed that mechanical stretch altered the localization, protein levels, and function of the cation-selective transient receptor potential channel (TRPC)-6 in atrial endocardial cells in humans, pigs, and mice. In endocardial/myocardial cross-talk studies, addition of media from porcine atrial endocardium (AE) cells altered the calcium (Ca²⁺) transient characteristics of human-induced pluripotent stem cell-derived cardiomyocytes. These changes did not occur with media from stretched AE cells. Our data suggested that endocardial TRPC-6-dependent paracrine signaling may modulate myocardial Ca²⁺ homeostasis under basal conditions and protect against stretch-induced atrial arrhythmias.

Keywords: AE, atrial endocardium; AF, atrial fibrillation; APB, aminoethoxydiphenyl borate; Ab, antibody; CM, cardiomyocyte; Ca2+, calcium; Dil-Ac-LDL, dil acetylated−low-density lipoprotein; ET, endothelin; HUVEC, human umbilical vein endothelial cell; OAG, 1-oleoyl-2-acetyl-sn-glycerol; TAC, thoracic aortic constriction; TRPC, transient receptor potential channel; Tet, tetanus toxin; [Ca2+]i, intracellular global Ca2+; atrial endocardium; endothelium; iPS, induced pluripotent stem; mechanical stretch; transient receptor potential channels.

Abstract

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