title: Intramyocardial BNP gene delivery improves cardiac function through distinct context-dependent mechanisms.
abstract: 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.
  
  
  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.
authors.affiliation: Institute of Biomedicine, Department of Pharmacology and Toxicology, Biocenter Oulu, Oulu, Finland.
authors.forename: Anne-Mari
authors.initials: AM
authors.lastname: Moilanen
authors.forename: Jaana
authors.initials: J
authors.lastname: Rysä
authors.forename: Erja
authors.initials: E
authors.lastname: Mustonen
authors.forename: Raisa
authors.initials: R
authors.lastname: Serpi
authors.forename: Jani
authors.initials: J
authors.lastname: Aro
authors.forename: Heikki
authors.initials: H
authors.lastname: Tokola
authors.forename: Hanna
authors.initials: H
authors.lastname: Leskinen
authors.forename: Aki
authors.initials: A
authors.lastname: Manninen
authors.forename: Jouko
authors.initials: J
authors.lastname: Levijoki
authors.forename: Olli
authors.initials: O
authors.lastname: Vuolteenaho
authors.forename: Heikki
authors.initials: H
authors.lastname: Ruskoaho
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000804:Angiotensin II / Q000009:adverse effects; D000818:Animals; D024061:Collagen Type III / Q000378:metabolism; D004195:Disease Models, Animal; D005355:Fibrosis / Q000503:physiopathology; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D006973:Hypertension / Q000139:chemically induced / Q000150:complications / Q000503:physiopathology; D008026:Ligation; D008297:Male; D009203:Myocardial Infarction / Q000150:complications / Q000209:etiology / Q000503:physiopathology; D020097:Natriuretic Peptide, Brain / Q000235:genetics* / Q000502:physiology*; D018919:Neovascularization, Physiologic / Q000502:physiology; D009946:Organothiophosphorus Compounds / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism; D018487:Ventricular Dysfunction, Left / Q000209:etiology / Q000503:physiopathology* / Q000628:therapy*; D020257:Ventricular Remodeling
chemical_list: D024061:Collagen Type III; D009946:Organothiophosphorus Compounds; D000804:Angiotensin II; D020097:Natriuretic Peptide, Brain; C002301:phosfolan; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases