In Mice Subjected to Chronic Stress, Exogenous cBIN1 Preserves Calcium-Handling Machinery and Cardiac Function

Yan Liu; Kang Zhou; Jing Li; Sosse Agvanian; Ana-Maria Caldaruse; Seiji Shaw; Tara C Hitzeman; Robin M Shaw; TingTing Hong

doi:10.1016/j.jacbts.2020.03.006

In Mice Subjected to Chronic Stress, Exogenous cBIN1 Preserves Calcium-Handling Machinery and Cardiac Function

JACC Basic Transl Sci. 2020 May 13;5(6):561-578. doi: 10.1016/j.jacbts.2020.03.006. eCollection 2020 Jun.

Authors

Yan Liu¹, Kang Zhou¹, Jing Li¹, Sosse Agvanian¹, Ana-Maria Caldaruse¹, Seiji Shaw¹, Tara C Hitzeman², Robin M Shaw², TingTing Hong^{1

3}

Affiliations

¹ Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California.
² Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, Utah.
³ Departments of Medicine, Cedars-Sinai Medical Center and UCLA, Los Angeles, California.

Abstract

Heart failure is an important, and growing, cause of morbidity and mortality. Half of patients with heart failure have preserved ejection fraction, for whom therapeutic options are limited. Here we report that cardiac bridging integrator 1 gene therapy to maintain subcellular membrane compartments within cardiomyocytes can stabilize intracellular distribution of calcium-handling machinery, preserving diastolic function in hearts stressed by chronic beta agonist stimulation and pressure overload. This study identifies that maintenance of intracellular architecture and, in particular, membrane microdomains at t-tubules, is important in the setting of sympathetic stress. Stabilization of membrane microdomains may be a pathway for future therapeutic development.

Keywords: AAV9, adeno-associated virus 9; ANOVA, analysis of variance; AR, adrenergic receptor; ATPase, adenosine triphosphatase; BW, body weight; CAMKII, Ca2+/calmodulin-dependent protein kinase; CMV, cytomegalovirus; Di-8-ANNEPs, 4-[2-[6-(Dioctylamino)-2-naphthalenyl]ethenyl]-1-(3-sulfopropyl)-pyridinium, inner salt; EC, excitation contraction; EDV, end diastolic volume; EF, ejection fraction; GFP, green fluorescent protein; HF, heart failure; HR, heart rate; HT, heterozygote; HW, heart weight; ISO, isoproterenol; LSD, least significant difference; LTCC, voltage-dependent L-type calcium channel; LV, left ventricular; LW, lung weight; PBS, phosphate-buffered saline; PKA, protein kinase A; PLN, phospholamban; RWT, relative wall thickness; RyR, ryanodine receptor; SD, standard deviation; SEM, standard error of the mean; SERCA2a, sarcoplasmic reticulum calcium ATPase pump 2a; SR, sarcoplasmic reticulum; STORM, stochastic optical reconstruction microscopy; TAC, transverse aortic constriction; TEM, transmission electron microscopy; WT, wild type; cBIN1, cardiac bridging integrator 1; diastolic dysfunction; heart failure; jSR, junctional sarcoplasmic reticulum; pressure overload; sympathetic overdrive; t-tubule; t-tubule, transverse-tubule; vg, vector genome.

Abstract

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