Cardiac phase-targeted dynamic load on left ventricle differentially regulates phase-sensitive gene expressions and pathway activation

Ken Onitsuka, Tomomi Ide, Shinobu Arai, Yuko Hata, Yoshinori Murayama, Kazuya Hosokawa, Takafumi Sakamoto, Tomoyuki Tobushi, Kazuo Sakamoto, Takeo Fujino, Kenji Sunagawa

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)

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 Ca2+/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.

Original languageEnglish
Pages (from-to)30-38
Number of pages9
JournalJournal of Molecular and Cellular Cardiology
Volume64
DOIs
Publication statusPublished - Nov 2013

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

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