title: Long-term cardiac pro-B-type natriuretic peptide gene delivery prevents the development of hypertensive heart disease in spontaneously hypertensive rats.
abstract: BACKGROUND
  Diastolic dysfunction associated with high blood pressure (BP) leads to cardiac remodeling and fibrosis and progression to congestive heart failure. B-type natriuretic peptide (BNP) has BP-lowering, antifibrotic, and antihypertrophic properties, which makes BNP an attractive agent for attenuating the adverse cardiac remodeling associated with hypertension. In the current study, we tested the effects of sustained cardiac proBNP gene delivery on BP, cardiac function, and remodeling in spontaneously hypertensive rats (SHR).
  
  
  RESULTS
  We used the myocardium-tropic adeno-associated virus serotype 9 (AAV9) vector to achieve continuously enhanced cardiac rat proBNP expression. In SHR, a single systemic administration of AAV9 vector allowed long-term cardiac BNP overexpression, resulting in reductions in systolic and diastolic BP for 9 months after injection. Left ventricular (LV) thickness, LV end-systolic dimensions, and LV mass were reduced, whereas ejection fraction was significantly increased, in BNP-treated compared with untreated SHR. Circumferential systolic strain and strain rate of the early phase of diastole were improved in BNP-treated compared with untreated SHR. Noncardiac overexpression of BNP via AAV2 vector was not associated with changes in BP and plasma BNP in SHR. Furthermore, normal Wistar rats injected with AAV9 proBNP vector showed significantly reduced heart weights 4 weeks after injection without BP reduction.
  
  
  CONCLUSIONS
  AAV9 vector facilitates sustained cardiac proBNP overexpression and improves LV function in hypertensive heart disease. Long-term proBNP delivery improved both systolic and diastolic function. The effects on cardiac structure and function occurred independently of BP-lowering effects in normal Wistar rats.
authors.affiliation: Molecular Medicine, Mayo Clinic, 200 First St. SW, Rochester, MN 55905, USA. ikeda.yasuhiro@mayo.edu
authors.forename: Alessandro
authors.initials: A
authors.lastname: Cataliotti
authors.forename: Jason M
authors.initials: JM
authors.lastname: Tonne
authors.forename: Diego
authors.initials: D
authors.lastname: Bellavia
authors.forename: Fernando L
authors.initials: FL
authors.lastname: Martin
authors.forename: Elise A
authors.initials: EA
authors.lastname: Oehler
authors.forename: Gerald E
authors.initials: GE
authors.lastname: Harders
authors.forename: Jarryd M
authors.initials: JM
authors.lastname: Campbell
authors.forename: Kaw-Whye
authors.initials: KW
authors.lastname: Peng
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Russell
authors.forename: Lorenzo S
authors.initials: LS
authors.lastname: Malatino
authors.forename: John C
authors.initials: JC
authors.lastname: Burnett
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Ikeda
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001794:Blood Pressure / Q000235:genetics; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics*; D004452:Echocardiography; D015316:Genetic Therapy / Q000379:methods*; D006333:Heart Failure / Q000000981:diagnostic imaging / Q000235:genetics / Q000517:prevention & control*; D006973:Hypertension / Q000235:genetics / Q000628:therapy*; D010957:Plasmids / Q000235:genetics; D011498:Protein Precursors / Q000235:genetics*; D051381:Rats; D011918:Rats, Inbred SHR; D017208:Rats, Wistar; D020257:Ventricular Remodeling / Q000235:genetics
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D011498:Protein Precursors; C426674:brain-derived neurotrophic factor precursor