title: Cardiac phase-targeted dynamic load on left ventricle differentially regulates phase-sensitive gene expressions and pathway activation.
abstract: The heart has remarkable capacity to adapt to mechanical load and to dramatically change its phenotype. The mechanism underlying such diverse phenotypic adaptations remains unknown. Since systolic overload induces wall thickening, while diastolic overload induces chamber enlargement, we hypothesized that cardiac phase-sensitive mechanisms govern the adaptation. We inserted a balloon into the left ventricle (LV) of a Langendorff perfused rat heart, and controlled LV volume (LVV) using a high performance servo-pump. We created isolated phasic systolic overload (SO) by isovolumic contraction (peak LV pressure >170mmHg) at unstressed diastolic LVV [end-diastolic pressure (EDP)=0mmHg]. We also created pure phasic diastolic overload (DO) by increasing diastolic LVV until EDP >40mmHg and unloading completely in systole. After 3hours under each condition, the myocardium was analyzed using DNA microarray. Gene expressions under SO and DO conditions were compared against unloaded control condition using gene ontology and pathway analysis (n=4 each). SO upregulated proliferation-related genes, whereas DO upregulated fibrosis-related genes (P<10(-5)). Both SO and DO upregulated genes related functionally to cardiac hypertrophy, although the gene profiles were totally different. Upstream regulators confirmed by Western blot indicated that SO activated extracellular signal-regulated kinase 1/2, c-Jun NH2-terminal kinase, and Ca(2+)/calmodulin-dependent protein kinase II (3.2-, 2.0-, and 4.7-fold versus control, P<0.05, n=5), whereas DO activated p38 (2.9-fold, P<0.01), which was consistent with the downstream gene expressions. In conclusion, pure isolated systolic and diastolic overload permits elucidation of cardiac phase-sensitive gene regulation. The genomic responses indicate that mechanisms governing the cardiac phase-sensitive adaptations are different.
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kyushu University, 3-1-1, Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Ken
authors.initials: K
authors.lastname: Onitsuka
authors.forename: Tomomi
authors.initials: T
authors.lastname: Ide
authors.forename: Shinobu
authors.initials: S
authors.lastname: Arai
authors.forename: Yuko
authors.initials: Y
authors.lastname: Hata
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Murayama
authors.forename: Kazuya
authors.initials: K
authors.lastname: Hosokawa
authors.forename: Takafumi
authors.initials: T
authors.lastname: Sakamoto
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Tobushi
authors.forename: Kazuo
authors.initials: K
authors.lastname: Sakamoto
authors.forename: Takeo
authors.initials: T
authors.lastname: Fujino
authors.forename: Kenji
authors.initials: K
authors.lastname: Sunagawa
mesh_terms: D000818:Animals; D001794:Blood Pressure; D016000:Cluster Analysis; D003971:Diastole; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006321:Heart / Q000502:physiology*; D006352:Heart Ventricles / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D008954:Models, Biological; D009206:Myocardium / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction; D013599:Systole
keywords: Cardiac phase; Isolated heart; Mechanical load; Microarray; Myocardial adaptation