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. 2005 Sep 21;23(1):18-27.
doi: 10.1152/physiolgenomics.00061.2005. Epub 2005 Jul 20.

Differential activation of stress-response signaling in load-induced cardiac hypertrophy and failure

Beverly A Rothermel  1 , Kambeez Berenji, Paul Tannous, William Kutschke, Asim Dey, Bridgid Nolan, Ki-Dong Yoo, Elaine Demetroulis, Michael Gimbel, Barry Cabuay, Mohsen Karimi, Joseph A Hill
Affiliations

Differential activation of stress-response signaling in load-induced cardiac hypertrophy and failure

Beverly A Rothermel et al. Physiol Genomics. .

Abstract

Hypertrophic growth of the myocardium occurs in most forms of heart failure and may contribute to the pathogenesis of the failure state. Little is known about the regulatory mechanisms governing the often-coexisting phenotypes of hypertrophy, systolic failure, and diastolic stiffness that characterize clinical disease. We hypothesized that intracellular signaling pathways are differentially activated by graded degrees of hemodynamic stress. To test this, we developed models of graded pressure stress in mice and used them to directly compare compensated hypertrophy and pressure-overload heart failure. Surgical interventions were designed to be similar, on either side of a threshold separating compensated from decompensated responses. Our findings revealed two dramatically different hypertrophic phenotypes with only modest differences in the activation of relevant intracellular signaling pathways. Furthermore, we uncovered a functional requirement of calcineurin signaling in each model such that calcineurin suppression blunted hypertrophic growth. Remarkably, in each case, suppression of calcineurin signaling was not associated with clinical deterioration or increased mortality. Profiles of stress-response signaling and Ca2+ handling differ between the steady-state, maintenance phases of load-induced cardiac hypertrophy and failure. This information may be useful in identifying novel targets of therapy in chronic disease.

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Figures

Fig. 1
Fig. 1
A: 4-chamber images of sham-operated, thoracic aortic banded (TAB), and severe TAB hearts. B: heart weights (HW) normalized to body weight (BW) or tibia length (T) are increased in mice with compensated hypertrophy (TAB) and heart failure (HF; severe TAB). C: hypertrophy of cardiac myocytes, measured as two-dimensional (2D) surface area, is similar in cells isolated from compensated hypertrophy (Comp Hyp) and HF myocardium.
Fig. 2
Fig. 2
Tumor necrosis factor (TNF) levels are significantly elevated (*P < 0.05 vs. sham) in HF mice.
Fig. 3
Fig. 3
A: measurements of distal and proximal carotid artery pressures demonstrate diminished pressure gradients in HF mice, consistent with decreased systolic performance. B: systolic function is preserved in mice subjected to TAB, whereas HF mice (severe TAB) manifest progressive declines in systolic performance. C: left ventricular (LV) size is preserved in all 3 models at 1 wk but progressively increases in HF mice.
Fig. 4
Fig. 4
Dot blots of steady-state transcript levels (representative of 3 independent measurements) reveal differential reactivation of the fetal gene program in Comp Hyp and HF hearts. Total RNA was isolated from the LV, and expression of hypertrophic marker genes was assessed by specific hybridization as previously described (29). ANF, atrial natriuretic factor; BNP, B-type natriuretic peptide; β-MHC, β-myosin heavy chain. *P < 0.05 vs. sham.
Fig. 5
Fig. 5
Western blot analysis of total protein expression (top blots and left bars in histogram) and phosphorylated (p) isoforms (bottom blots and right bars in histogram) reveal selective activation of ERK (A) and JNK (B) in HF. Evidence of significant activation of p38 (C) and Akt (D) was not obtained. Representative data from 3 independent measurements are illustrated. *P < 0.05 vs. sham.
Fig. 6
Fig. 6
Representative Western blot analysis of calsequestrin (CSQ; A), calcineurin A subunit (CnA; B), phospholamban (PLB) and Ser16-pPLB (Phos-S16 PLB; C), and the exon 4 isoform of modulatory calcineurin-interacting protein (MCIP; D) in Comp Hyp and HF hearts. Data illustrated are representative of 3 independent measurements. *P < 0.05 vs. sham.
Fig. 7
Fig. 7
LV weight normalized to body weight or tibia length in wild-type (WT) animals subjected to sham surgery (n = 5) or severe TAB as listed [WT, n = 12; cyclosporin A (CsA), n = 8; MCIP, n = 12]. *P < 0.01 vs. sham; **P < 0.05 vs. vehicle-treated WT; ***P < 0.01 vs. vehicle-treated WT.
Fig. 8
Fig. 8
Kaplan-Meier survival analysis. A: Comp Hyp mice (▲, n = 262) and Comp Hyp mice treated with CsA (△, n = 128) manifested similar survival. In contrast, HF mice treated with CsA (□, n = 59) manifested worse survival compared with HF mice treated with vehicle (■, n = 268). B: MCIP1 transgenic mice subjected to severe TAB (□, n = 14) survived similarly to WT littermates subjected to similar surgery (■, n = 5).
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References

    1. American Heart Association. Heart Disease and Stroke Statistics–2004 Update. Dallas, TX: American Heart Association; 2003.
    1. Berenji K, Drazner MH, Rothermel BA, Hill JA. Does load-induced ventricular hypertrophy progress to systolic heart failure? Am J Physiol Heart Circ Physiol. 2005;289:H8–H16. - PubMed
    1. Bowling N, Walsh RA, Song GJ, Estridge T, Sandusky GE, Fouts RL, Mintze K, Pickard T, Roden R, Bristow MR, Sabbah HN, Mizrahi JL, Gromo G, King GL, Vlahos CJ. Increased protein kinase C activity and expression of Ca2+-sensitive isoforms in the failing human heart. Circulation. 1999;99:384–391. - PubMed
    1. Braz JC, Gregory K, Pathak A, Zhao W, Sahin B, Klevitsky R, Kimball TF, Lorenz JN, Nairn AC, Liggett SB, Bodi I, Wang S, Schwartz A, Lakatta EG, DePaoli-Roach AA, Robbins J, Hewett TE, Bibb JA, Westfall MV, Kranias EG, Molkentin JD. PKC-alpha regulates cardiac contractility and propensity toward heart failure. Nat Med. 2004;10:248–254. - PubMed
    1. Brown DW, Giles WH, Croft JB. Left ventricular hypertrophy as a predictor of coronary heart disease mortality and the effect of hypertension. Am Heart J. 2000;140:848–856. - PubMed

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