Cardiac S100A1 protein levels determine contractile performance and propensity toward heart failure after myocardial infarction.
BACKGROUND
Diminished cardiac S100A1 protein levels are characteristic of ischemic and dilated human cardiomyopathy. Because S100A1 has recently been identified as a Ca2+-dependent inotropic factor in the heart, this study sought to explore the pathophysiological relevance of S100A1 levels in development and progression of postischemic heart failure (HF).


RESULTS
S100A1-transgenic (STG) and S100A1-knockout (SKO) mice were subjected to myocardial infarction (MI) by surgical left anterior descending coronary artery ligation, and survival, cardiac function, and remodeling were compared with nontransgenic littermate control (NLC) and wild-type (WT) animals up to 4 weeks. Although MI size was similar in all groups, infarcted S100A1-deficient hearts (SKO-MI) responded with acute contractile decompensation and accelerated transition to HF, rapid onset of cardiac remodeling with augmented apoptosis, and excessive mortality. NLC/WT-MI mice, displaying a progressive decrease in cardiac S100A1 expression, showed a later onset of cardiac remodeling and progression to HF. Infarcted S100A1-overexpressing hearts (STG-MI), however, showed preserved global contractile performance, abrogated apoptosis, and prevention from cardiac hypertrophy and HF with superior survival compared with NLC/WT-MI and SKO-MI. Both Gq-protein-dependent signaling and protein kinase C activation resulted in decreased cardiac S100A1 mRNA and protein levels, whereas Gs-protein-related signaling exerted opposite effects on cardiac S100A1 abundance. Mechanistically, sarcoplasmic reticulum Ca2+ cycling and beta-adrenergic signaling were severely impaired in SKO-MI myocardium but preserved in STG-MI.


CONCLUSIONS
Our novel proof-of-concept study provides evidence that downregulation of S100A1 protein critically contributes to contractile dysfunction of the diseased heart, which is potentially responsible for driving the progressive downhill clinical course of patients with HF.
Most
Patrick
P
Center for Translational Medicine, Department of Medicine, Thomas Jefferson University, Philadelphia, PA 19107, USA. patrick.most@jefferson.edu
Seifert
Hanna
H
Gao
Erhe
E
Funakoshi
Hajime
H
Völkers
Mirko
M
Heierhorst
Jörg
J
Remppis
Andrew
A
Pleger
Sven T
ST
DeGeorge
Brent R
BR
Eckhart
Andrea D
AD
Feldman
Arthur M
AM
Koch
Walter J
WJ
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D000252:Calcium-Transporting ATPases / Q000235:genetics / Q000378:metabolism; D002303:Cardiac Output, Low / Q000209:etiology / Q000503:physiopathology* / Q000517:prevention & control; D000242:Cyclic AMP / Q000502:physiology; D018450:Disease Progression; D015536:Down-Regulation; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009200:Myocardial Contraction / Q000235:genetics / Q000502:physiology*; D009203:Myocardial Infarction / Q000150:complications / Q000473:pathology / Q000503:physiopathology*; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011943:Receptors, Adrenergic, beta / Q000502:physiology; D009418:S100 Proteins / Q000235:genetics / Q000378:metabolism*; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D020257:Ventricular Remodeling / Q000502:physiology
D012333:RNA, Messenger; D011943:Receptors, Adrenergic, beta; D009418:S100 Proteins; C110294:S100A1 protein; D000242:Cyclic AMP; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D019205:GTP-Binding Protein alpha Subunits, Gs; D000252:Calcium-Transporting ATPases