Targeting Calpain for Heart Failure Therapy: Implications From Multiple Murine Models

Yihui Wang; Biyi Chen; Chun-Kai Huang; Ang Guo; Jennifer Wu; Xiaoming Zhang; Rong Chen; Cheng Chen; William Kutschke; Robert M Weiss; Ryan L Boudreau; Kenneth B Margulies; Jiang Hong; Long-Sheng Song

doi:10.1016/j.jacbts.2018.05.004

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Targeting Calpain for Heart Failure Therapy: Implications From Multiple Murine Models

Journal article

Open access

Peer reviewed

Targeting Calpain for Heart Failure Therapy: Implications From Multiple Murine Models

Yihui Wang, Biyi Chen, Chun-Kai Huang, Ang Guo, Jennifer Wu, Xiaoming Zhang, Rong Chen, Cheng Chen, William Kutschke, Robert M Weiss, …

JACC. Basic to translational science, Vol.3(4), pp.503-517

08/01/2018

DOI: 10.1016/j.jacbts.2018.05.004

PMID: 30175274

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Abstract

• Calpain is hyperactivated in human failing hearts and rodent heart failure models of different etiologies. • Inhibition of calpain activity with MDL-28170 protects against cardiac dysfunction by preserving JP2 expression and T-tubule ultrastructural integrity in murine models of heart failure. • Overexpression of JP2 delays the onset of early cardiac sudden death and heart failure, induced by calpain overactivation. Heart failure remains a major cause of morbidity and mortality in developed countries. There is still a strong need to devise new mechanism-based treatments for heart failure. Numerous studies have suggested the importance of the Ca 2+ -dependent protease calpain in cardiac physiology and pathology. However, no drugs are currently under development or testing in human patients to target calpain for heart failure treatment. Herein the data demonstrate that inhibition of calpain activity protects against deleterious ultrastructural remodeling and cardiac dysfunction in multiple rodent models of heart failure, providing compelling evidence that calpain inhibition is a promising therapeutic strategy for heart failure treatment.

heart failure

RV, right ventricular

calcium

TAB, transverse aortic banding

WT, wild-type

LV, left ventricle

SR, sarcoplasmic reticulum

PRECLINICAL RESEARCH

TTpower, strength of regularity of the T-tubule system

ventricular

MI, myocardial infarction

E-C coupling, excitation-contraction coupling

JP2, junctophilin-2

calpain

IP, intraperitoneally

T-tubules

ISO, isoproterenol

JP2-OE, junctophilin-2 overexpressing

T-tubule, transverse tubule

EF, ejection fraction

CAPN1-OE, calpain-1 overexpressing

excitation-contraction coupling

Details

Title: Subtitle: Targeting Calpain for Heart Failure Therapy: Implications From Multiple Murine Models
Creators: Yihui Wang - Shanghai General Hospital, Shanghai Jiaotong University, Shanghai, China
Biyi Chen - Division of Cardiovascular Medicine, Department of Internal Medicine & François M. Abboud Cardiovascular Research Center, University of Iowa Carver College of Medicine; Iowa City, Iowa
Chun-Kai Huang - Shanghai General Hospital, Shanghai Jiaotong University, Shanghai, China
Ang Guo - Division of Cardiovascular Medicine, Department of Internal Medicine & François M. Abboud Cardiovascular Research Center, University of Iowa Carver College of Medicine; Iowa City, Iowa
Jennifer Wu - Division of Cardiovascular Medicine, Department of Internal Medicine & François M. Abboud Cardiovascular Research Center, University of Iowa Carver College of Medicine; Iowa City, Iowa
Xiaoming Zhang - Division of Cardiovascular Medicine, Department of Internal Medicine & François M. Abboud Cardiovascular Research Center, University of Iowa Carver College of Medicine; Iowa City, Iowa
Rong Chen - Shanghai General Hospital, Shanghai Jiaotong University, Shanghai, China
Cheng Chen - Shanghai General Hospital, Shanghai Jiaotong University, Shanghai, China
William Kutschke - Division of Cardiovascular Medicine, Department of Internal Medicine & François M. Abboud Cardiovascular Research Center, University of Iowa Carver College of Medicine; Iowa City, Iowa
Robert M Weiss - Division of Cardiovascular Medicine, Department of Internal Medicine & François M. Abboud Cardiovascular Research Center, University of Iowa Carver College of Medicine; Iowa City, Iowa
Ryan L Boudreau - Division of Cardiovascular Medicine, Department of Internal Medicine & François M. Abboud Cardiovascular Research Center, University of Iowa Carver College of Medicine; Iowa City, Iowa
Kenneth B Margulies - Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania
Jiang Hong - Shanghai General Hospital, Shanghai Jiaotong University, Shanghai, China
Long-Sheng Song - Division of Cardiovascular Medicine, Department of Internal Medicine & François M. Abboud Cardiovascular Research Center, University of Iowa Carver College of Medicine; Iowa City, Iowa
Resource Type: Journal article
Publication Details: JACC. Basic to translational science, Vol.3(4), pp.503-517
DOI: 10.1016/j.jacbts.2018.05.004
PMID: 30175274
NLM abbreviation: JACC Basic Transl Sci
ISSN: 2452-302X
eISSN: 2452-302X
Publisher: Elsevier
Language: English
Date published: 08/01/2018
Academic Unit: The University of Iowa Institute for Vision Research; Iowa Neuroscience Institute; Cardiovascular Medicine; Fraternal Order of Eagles Diabetes Research Center; Biochemistry and Molecular Biology; Internal Medicine
Record Identifier: 9984065387002771

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