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Intramyocardial BNP gene delivery improves cardiac function through distinct context-dependent mechanisms.
MedLine Citation:
PMID:  21558448     Owner:  NLM     Status:  MEDLINE    
BACKGROUND: B-type natriuretic peptide (BNP) is an endogenous peptide produced under physiological and pathological conditions mainly by ventricular myocytes. It has natriuretic, diuretic, blood pressure-lowering, and antifibrotic actions that could mediate cardiorenal protection in cardiovascular diseases. In the present study, we used BNP gene transfer to examine functional and structural effects of BNP on left ventricular (LV) remodeling.
METHODS AND RESULTS: Human BNP was overexpressed by using adenovirus-mediated gene delivery in normal rat hearts and in hearts during the remodeling process after infarction and in an experimental model of angiotensin II-mediated hypertension. In healthy hearts, BNP gene delivery into the anterior wall of the LV decreased myocardial fibrosis (P<0.01, n=7 to 8) and increased capillary density (P<0.05, n=7 to 8) associated with a 7.3-fold increase in LV BNP peptide levels. Overexpression of BNP improved LV fractional shortening by 22% (P<0.05, n=6 to 7) and ejection fraction by 19% (P<0.05, n=6 to 7) after infarction. The favorable effect of BNP gene delivery on cardiac function after infarction was associated with normalization of cardiac sarcoplasmic reticulum Ca(2+)-ATPase expression and phospholamban Thr17-phosphorylation. BNP gene delivery also improved fractional shortening and ejection fraction in angiotensin II-mediated hypertension as well as decreased myocardial fibrosis and LV collagen III mRNA levels but had no effect on angiogenesis or Ca(2+)-ATPase expression and phospholamban phosphorylation.
CONCLUSIONS: Local intramyocardial BNP gene delivery improves cardiac function and attenuates adverse postinfarction and angiotensin II-induced remodeling. These results also indicate that myocardial BNP has pleiotropic, context-dependent, favorable actions on cardiac function and suggest that BNP acts locally as a key mechanical load-activated regulator of angiogenesis and fibrosis.
Anne-Mari Moilanen; Jaana Rysä; Erja Mustonen; Raisa Serpi; Jani Aro; Heikki Tokola; Hanna Leskinen; Aki Manninen; Jouko Levijoki; Olli Vuolteenaho; Heikki Ruskoaho
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2011-05-10
Journal Detail:
Title:  Circulation. Heart failure     Volume:  4     ISSN:  1941-3297     ISO Abbreviation:  Circ Heart Fail     Publication Date:  2011 Jul 
Date Detail:
Created Date:  2011-07-20     Completed Date:  2011-09-15     Revised Date:  2011-10-27    
Medline Journal Info:
Nlm Unique ID:  101479941     Medline TA:  Circ Heart Fail     Country:  United States    
Other Details:
Languages:  eng     Pagination:  483-95     Citation Subset:  IM    
Institute of Biomedicine, Department of Pharmacology and Toxicology, Biocenter Oulu, Oulu, Finland.
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MeSH Terms
Adenoviridae / genetics
Angiotensin II / adverse effects
Collagen Type III / metabolism
Disease Models, Animal
Fibrosis / physiopathology
Gene Therapy / methods*
Gene Transfer Techniques
Hypertension / chemically induced,  complications,  physiopathology
Myocardial Infarction / complications,  etiology,  physiopathology
Natriuretic Peptide, Brain / genetics*,  physiology*
Neovascularization, Physiologic / physiology
Organothiophosphorus Compounds / metabolism
Rats, Sprague-Dawley
Sarcoplasmic Reticulum Calcium-Transporting ATPases / metabolism
Ventricular Dysfunction, Left / etiology,  physiopathology*,  therapy*
Ventricular Remodeling*
Reg. No./Substance:
0/Collagen Type III; 0/Organothiophosphorus Compounds; 11128-99-7/Angiotensin II; 114471-18-0/Natriuretic Peptide, Brain; 947-02-4/phosfolan; EC Reticulum Calcium-Transporting ATPases

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