Document Detail


S100A1: a multifaceted therapeutic target in cardiovascular disease.
MedLine Citation:
PMID:  20645037     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Cardiovascular disease is the leading cause of death worldwide, showing a dramatically growing prevalence. It is still associated with a poor clinical prognosis, indicating insufficient long-term treatment success of currently available therapeutic strategies. Investigations of the pathomechanisms underlying cardiovascular disorders uncovered the Ca(2+) binding protein S100A1 as a critical regulator of both cardiac performance and vascular biology. In cardiomyocytes, S100A1 was found to interact with both the sarcoplasmic reticulum ATPase (SERCA2a) and the ryanodine receptor 2 (RyR2), resulting in substantially improved Ca(2+) handling and contractile performance. Additionally, S100A1 has been described to target the cardiac sarcomere and mitochondria, leading to reduced pre-contractile passive tension as well as enhanced oxidative energy generation. In endothelial cells, molecular analyses revealed a stimulatory effect of S100A1 on endothelial NO production by increasing endothelial nitric oxide synthase activity. Emphasizing the pathophysiological relevance of S100A1, myocardial infarction in S100A1 knockout mice resulted in accelerated transition towards heart failure and excessive mortality in comparison with wild-type controls. Mice lacking S100A1 furthermore displayed significantly elevated blood pressure values with abrogated responsiveness to bradykinin. On the other hand, numerous studies in small and large animal heart failure models showed that S100A1 overexpression results in reversed maladaptive myocardial remodeling, long-term rescue of contractile performance, and superior survival in response to myocardial infarction, indicating the potential of S100A1-based therapeutic interventions. In summary, elaborate basic and translational research established S100A1 as a multifaceted therapeutic target in cardiovascular disease, providing a promising novel therapeutic strategy to future cardiologists.
Authors:
David Rohde; Julia Ritterhoff; Mirko Voelkers; Hugo A Katus; Thomas G Parker; Patrick Most
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Review     Date:  2010-07-20
Journal Detail:
Title:  Journal of cardiovascular translational research     Volume:  3     ISSN:  1937-5395     ISO Abbreviation:  J Cardiovasc Transl Res     Publication Date:  2010 Oct 
Date Detail:
Created Date:  2010-09-07     Completed Date:  2010-12-28     Revised Date:  2013-05-29    
Medline Journal Info:
Nlm Unique ID:  101468585     Medline TA:  J Cardiovasc Transl Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  525-37     Citation Subset:  IM    
Affiliation:
Laboratory for Molecular and Translational Cardiology, Division of Cardiology, Department of Internal Medicine III, University of Heidelberg, INF 350, 69120 Heidelberg, Germany.
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MeSH Terms
Descriptor/Qualifier:
Animals
Cardiovascular Agents / therapeutic use*
Cardiovascular Diseases / genetics,  metabolism,  physiopathology,  therapy*
Endothelial Cells / drug effects,  metabolism
Genetic Therapy*
Humans
Models, Molecular
Molecular Targeted Therapy
Myocytes, Cardiac / drug effects,  metabolism
Protein Conformation
S100 Proteins / chemistry,  genetics,  metabolism*
Signal Transduction
Translational Medical Research
Grant Support
ID/Acronym/Agency:
HL092130-02S1/HL/NHLBI NIH HHS; R01 HL092130-01/HL/NHLBI NIH HHS; //Canadian Institutes of Health Research
Chemical
Reg. No./Substance:
0/Cardiovascular Agents; 0/S100 Proteins; 0/S100A1 protein
Comments/Corrections

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