title: Intermittent pressure overload triggers hypertrophy-independent cardiac dysfunction and vascular rarefaction.
abstract: For over a century, there has been intense debate as to the reason why some cardiac stresses are pathological and others are physiological. One long-standing theory is that physiological overloads such as exercise are intermittent, while pathological overloads such as hypertension are chronic. In this study, we hypothesized that the nature of the stress on the heart, rather than its duration, is the key determinant of the maladaptive phenotype. To test this, we applied intermittent pressure overload on the hearts of mice and tested the roles of duration and nature of the stress on the development of cardiac failure. Despite a mild hypertrophic response, preserved systolic function, and a favorable fetal gene expression profile, hearts exposed to intermittent pressure overload displayed pathological features. Importantly, intermittent pressure overload caused diastolic dysfunction, altered beta-adrenergic receptor (betaAR) function, and vascular rarefaction before the development of cardiac hypertrophy, which were largely normalized by preventing the recruitment of PI3K by betaAR kinase 1 to ligand-activated receptors. Thus stress-induced activation of pathogenic signaling pathways, not the duration of stress or the hypertrophic growth per se, is the molecular trigger of cardiac dysfunction.
authors.affiliation: Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: Cinzia
authors.initials: C
authors.lastname: Perrino
authors.forename: Sathyamangla V
authors.initials: SV
authors.lastname: Naga Prasad
authors.forename: Lan
authors.initials: L
authors.lastname: Mao
authors.forename: Takahisa
authors.initials: T
authors.lastname: Noma
authors.forename: Zhen
authors.initials: Z
authors.lastname: Yan
authors.forename: Hyung-Suk
authors.initials: HS
authors.lastname: Kim
authors.forename: Oliver
authors.initials: O
authors.lastname: Smithies
authors.forename: Howard A
authors.initials: HA
authors.lastname: Rockman
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000378:metabolism; D000818:Animals; D001794:Blood Pressure / Q000502:physiology*; D001808:Blood Vessels / Q000473:pathology / Q000502:physiology / Q000503:physiopathology; D002303:Cardiac Output, Low; D006332:Cardiomegaly / Q000473:pathology / Q000503:physiopathology; D002478:Cells, Cultured; D004452:Echocardiography; D005260:Female; D005786:Gene Expression Regulation; D006321:Heart / Q000502:physiology*; D006439:Hemodynamics; D006801:Humans; D017379:Hypertrophy, Left Ventricular; D008790:Metoprolol / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009206:Myocardium / Q000166:cytology / Q000378:metabolism / Q000473:pathology*; D010641:Phenotype; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D013312:Stress, Physiological; D051552:beta-Adrenergic Receptor Kinases / Q000378:metabolism
chemical_list: D000319:Adrenergic beta-Antagonists; D008790:Metoprolol; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011943:Receptors, Adrenergic, beta; D051552:beta-Adrenergic Receptor Kinases