Download Elevated Ventricular Wall Stress Disrupts Cardiomyocyte T

Elevated Ventricular Wall Stress Disrupts Cardiomyocyte T-tubular Structure and Ca2+ Homeostasis
Ruud M1,2, Frisk M1,2, Espe EK 1,2, Aronsen M1,2,3, Norseng PA1,2, Sjaastad I1,2,3, Sejersted O1,2,
Christensen G1,2, Louch WE1,2
1
Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo,
Norway
2
K.G. Jebsen Cardiac Research Center and Center for Heart Failure Research, University of Oslo,
Oslo, Norway
3
Bjørknes College, Oslo, Norway
T-tubules are critical for efficient excitation-contraction coupling in cardiomyocytes, and their
disorganization during heart failure weakens contraction. The precise mechanism and signaling
underlying such t-tubular remodeling are largely unknown, but increased ventricular load has been
suggested to be centrally involved (Ibrahim et al., Cardiovasc Res, 2013). We presently hypothesized
that ventricular wall stress is a specific trigger regulating t-tubule remodeling. In failing post-infarction
rat hearts, we employed MRI-imaging and blood pressure measurements to estimate wall stress
across the heart. Wall stress was higher in failing hearts than sham-operated controls, and was
particularly elevated proximal to the infarct. Wall stress measurements were closely correlated with
disruption of cardiomyocyte t-tubule structure and function, as marked disruption of t-tubule
organization, Ca2+ homeostasis, and local contractility were observed near the infarct. Regional ttubule loss was associated with downregulation of Junctophilin-2 (JP2), an established t-tubule anchor
(Wei et al., Circ Res, 2010). To investigate whether wall stress directly triggers t-tubule remodeling we
mounted left ventricular rat papillary muscles in a myobath system and stretched to mimic in vivo wall
stress levels (0.5 Hz stimulation, 48 hours). Muscles exposed to modest stretch (low diastolic wall
stress ≈ 4 kN/m2) exhibited well-maintained t-tubule organization during culture. Exposure to high
stretch (wall stress ≈ 15-20 kN/m2) approximating that observed proximal to the infarction of failing
hearts triggered significant downregulation of JP2 and t-tubule loss. Although the calcineurin-NFAT
pathway has been suggested to regulate JP2 expression via miR-24 (Xu et al., Circ Res, 2012), we
did not observe wall stress-dependent regulation of miR-24 or RCAN1. This suggests the involvement
of a new unknown signaling pathway in mediating wall stress-induced t-tubule remodeling which
contributes to heart failure progression. Our findings also suggest a possible mechanism by which
unloading of the heart is beneficial in heart failure patients.