Intermittent pressure overload triggers hypertrophy-independent cardiac dysfunction and vascular rarefaction.
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.
Perrino
Cinzia
C
Duke University Medical Center, Durham, North Carolina 27710, USA.
Naga Prasad
Sathyamangla V
SV
Mao
Lan
L
Noma
Takahisa
T
Yan
Zhen
Z
Kim
Hyung-Suk
HS
Smithies
Oliver
O
Rockman
Howard A
HA
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
D000319:Adrenergic beta-Antagonists; D008790:Metoprolol; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011943:Receptors, Adrenergic, beta; D051552:beta-Adrenergic Receptor Kinases