Transgenic system for conditional induction and rescue of chronic myocardial hibernation provides insights into genomic programs of hibernation

May, Dalit; Gilon, Dan; Djonov, Valentin; Itin, Ahuva; Lazarus, Alon; Gordon, Oren; Rosenberger, Christian; Keshet, Eli (2008). Transgenic system for conditional induction and rescue of chronic myocardial hibernation provides insights into genomic programs of hibernation. Proceedings of the National Academy of Sciences of the United States of America - PNAS, 105(1), pp. 282-7. Washington, D.C.: National Academy of Sciences NAS 10.1073/pnas.0707778105

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A key energy-saving adaptation to chronic hypoxia that enables cardiomyocytes to withstand severe ischemic insults is hibernation, i.e., a reversible arrest of contractile function. Whereas hibernating cardiomyocytes represent the critical reserve of dysfunctional cells that can be potentially rescued, a lack of a suitable animal model has hampered insights on this medically important condition. We developed a transgenic mouse system for conditional induction of long-term hibernation and a system to rescue hibernating cardiomyocytes at will. Via myocardium-specific induction (and, in turn, deinduction) of a VEGF-sequestering soluble receptor, we show that VEGF is indispensable for adjusting the coronary vasculature to match increased oxygen consumption and exploit this finding to generate a hypoperfused heart. Importantly, ensuing ischemia is tunable to a level at which large cohorts of cardiomyocytes are driven to enter a hibernation mode, without cardiac cell death. Relieving the VEGF blockade even months later resulted in rapid revascularization and full recovery of contractile function. Furthermore, we show that left ventricular remodeling associated with hibernation is also fully reversible. The unique opportunity to uncouple hibernation from other ischemic heart phenotypes (e.g., infarction) was used to determine the genetic program of hibernation; uncovering hypoxia-inducible factor target genes associated with metabolic adjustments and induced expression of several cardioprotective genes. Autophagy, specifically self-digestion of mitochondria, was identified as a key prosurvival mechanism in hibernating cardiomyocytes. This system may lend itself for examining the potential utility of treatments to rescue dysfunctional cardiomyocytes and reverse maladaptive remodeling.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Anatomy

UniBE Contributor:

Djonov, Valentin

ISSN:

0027-8424

ISBN:

18162550

Publisher:

National Academy of Sciences NAS

Language:

English

Submitter:

Factscience Import

Date Deposited:

04 Oct 2013 14:56

Last Modified:

04 May 2014 23:16

Publisher DOI:

10.1073/pnas.0707778105

PubMed ID:

18162550

Web of Science ID:

000252435300053

URI:

https://boris.unibe.ch/id/eprint/23709 (FactScience: 43543)

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