Myocardial Hypertrophic Preconditioning Attenuates Cardiomyocyte Hypertrophy and Slows Progression to Heart Failure Through Upregulation of S100A8/A9
Background—Transient preceding brief ischemia provides potent cardioprotection against subsequent long ischemia, termed ischemic preconditioning. Here we hypothesized that transient short-term hypertrophic stimulation would induce the expression of hypertrophy regression genes and render the heart resistant to subsequent hypertrophic stress as well as slowing progression to heart failure.
Methods and Results—Cardiomyocyte hypertrophy was induced in mice by either transverse aortic constriction (TAC) or an infusion of phenylephrine (PE), and in neonatal rat ventricular cardiomyocytes (NRVCs) by norepinephrine (NE) exposures. In the preconditioning groups, hypertrophic stimulation was provided for 1-7 days and then withdrawn for several days by either aortic debanding or discontinuing PE or NE treatment, followed by subsequent re-exposure to the hypertrophic stimulus for the same period as in the control group. One or 6 weeks after TAC, the heart/body weight ratio was lower in the preconditioning group than in the control group, while the lung/body weight ratio was significantly decreased 6 weeks after TAC. Similar results were obtained in mice receiving PE infusion and NRVCs stimulated with NE. Both mRNA and protein expression of S100A8 and S100A9 showed significant upregulation after the removal of hypertrophic stimulation and persisted for 6 weeks in response to re-imposition of TAC. The treatment with recombinant S100A8/A9 inhibited NE-induced myocyte hypertrophy, and reduced the expression of calcineurin and NFATc3, while silencing of S100A8/A9 prevented such changes.
Conclusions—Preconditioning with prohypertrophic factors exerts an antihypertrophic effect and slows the progression of heart failure, indicating the existence of the phenomenon for hypertrophic preconditioning.
- Received October 15, 2014.
- Revision received January 30, 2015.
- Accepted February 26, 2015.
Circulation is published on behalf of the American Heart Association, Inc., by Wolters Kluwer. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial-NoDervis License (http://creativecommons.org/licenses/by-nc-nd/3.0/), which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited, the use is noncommercial, and no modifications or adaptations are made.