Abstract 17088: Myocardial Hypertrophic Preconditioning Attenuates Cardiomyocyte Hypertrophy and Slows the Progression to Heart Failure through Upregulation of S100A8/A9
Background: It is known that intermittent neurohormonal stimulation in sportsmen leads to physiological myocardial hypertrophy (MH), while persistent stimulation in patients results in pathological MH, hinting a phenomenon of myocardial hypertrophic preconditioning (MHP). We hypothesized that brief episodes of hypertrophic stimulation would render the heart resistant to subsequent hypertrophic stress and slow the progression of heart failure (HF). The objective in this study is to prove the phenomenon of MHP and investigate the possible mechanism.
Methods and Results: Cardiomyocyte hypertrophy was induced in C57BL/6 mice by transverse aortic constriction (TAC) or infusion of phenylephrine (PE) and in cultured neonatal rat cardiomyocytes (NRC) by PE stimulation. In the preconditioning (PREC) groups, hypertrophic stimuli were added for 1-7 d, and then removed for several days by debanding or discontinuing PE stimulation, and subsequently re-exposure to hypertrophic stimuli for the same periods as the control groups. One wk after TAC, heart to body weight ratio (HW/BW) was lower in PREC group than in control group (5.35±0.17 vs. 5.99±0.22 mg/g,P=0.014). Six wks after TAC, HW/BW (5.43±0.11 vs. 7.16±0.33 mg/g, P=0.004), lung weight/BW (6.15±0.11, vs. 9.88±1.00 mg/g, P=0.046) and echocardiographic LV dimensions were significantly smaller in PREC group than in control group. Expression of ANP and β-MHC was down-regulated by PREC. Similar results were obtained in PE stimulated mice and NRC. In regard to the underlying mechanism, we found that the mRNA and protein expression of damage-associated molecular pattern molecules S100A8/A9 during the stimuli removal were significantly upregulated. Treatment with S100A8/A9 inhibited PE- or TAC-induced myocyte hypertrophy, reduced the pro-collagen I and III gene expression as well as the protein expression of calcineurin and the translocation of NFAT.
Conclusion. We provided the first evidence that preconditioning by prohypertrophic factors renders the heart resistant to subsequent hypertrophic stress and slows the progression of HF, indicating the presence of MHP. S100A8/A9 mediated suppression of the calcineurin/NFAT pathway accounts for partly the cardioprotective of MHP.
- © 2012 by American Heart Association, Inc.