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Review
. 2002 Apr;109(7):849-55.
doi: 10.1172/JCI15380.

Mixed signals in heart failure: cancer rules

Masahiko Hoshijima  1 , Kenneth R Chien
Affiliations
Review

Mixed signals in heart failure: cancer rules

Masahiko Hoshijima et al. J Clin Invest. 2002 Apr.
No abstract available

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Figures

Figure 1
Figure 1
Mechanical stress–induced transmembrane signaling and integrated phenotypes of failing heart. The activation profiles of various signaling cascades and time-dependent changes in phenotypic features of heart failure are illustrated based on our previous studies (5) and unpublished observations. The lower panel shows the expression profiles of selected genes from publications in both human and animal studies. See supplemental reading list (www.jci.org/cgi/content/full/109/7/849/DC1) for detailed references.
Figure 2
Figure 2
New therapeutic targets of heart failure in regulatory pathways of excitation-contraction coupling. Excitation-contraction coupling and its regulation by Gs-activating G protein–coupling receptor (GPCR) and A-kinase signaling. A series of genes have been subjected to target validation analysis via transgenic and somatic gene transfer studies with a variety of viral vector systems and protocols. 1. β2-adrenergic receptor (β2AR). β2AR transgenic (β2AR-TG) mice display a hypertrophic cardiomyopathy phenotype and do not rescue the phenotype of failing muscle-specific LIM-only protein knockout (MLPKO) mice. β2AR-TG mice fail to rescue the HCM phenotype of R403QαMHC-TG mice. Percutaneous or intramuscular Adeno/β2AR delivery results in enhanced contractility in normal rabbit or cardiomyopathic hamsters. 2. βARK inhibitor (βARKct). βARKct-TG mice partially rescue cardiomyopathic phenotypes of MLPKO mice and R403QαMHC-TG mice. Adeno/βARKct improves contractility and delays heart failure development in post–myocardial infarction rabbits. 3. Adenylyl cyclase type VI (AC-typeVI). AC-typeVI–TG mice rescue heart failure in Gq-TG mice. Percutaneous Adeno/AC-typeVI delivery enhances cardiac contractility in normal pigs. 4. Phosphodiesterase. Several human clinical trials have confirmed that phosphodiesterase’s pharmacological inhibition improves cardiac function, although at the risk of decreased long-term survival; current clinical use is primarily confined to end-stage heart failure awaiting transplantation. 5. SERCA2: SERCA2-TG mice are hyperkinetic, whereas heterozygous null animals are hypokinetic. Adeno/SERCA2 gene delivery improves cardiac contractility and prognosis of postaortic banded rats. SERCA1: SERCA1-TG mice are hyperkinetic. Adeno/SERCA1 has been used to support intramuscular delivery of Kv2.1 in normal guinea pig hearts. 6. Phospholamban (PLN). PLN-TG mice are hypokinetic, whereas knockout mice are hyperkinetic. Adeno and AAV/mutant PLN suppress cardiomyopathic hamster heart failure development. 7. FKBP12.6: In vitro Adeno/FKBP12.6–transfected cardiomyocyte increases contractility. Parvalbumin: Adeno/parvalbumin intramuscular delivery enhances normal rat cardiac relaxation. GRK, GPCR kinase; ICa,L, L-type calcium channel (dihydropyridine receptor); RyR, ryanodine receptor; JP-2, junctophilin-2. See supplemental reading list (www.jci.org/cgi/content/full/109/7/849/DC1) for detailed references.
See this image and copyright information in PMC

References

    1. Hunter, J.J., Grace, A., and Chien, K.R. 1999. Molecular and cellular biology of cardiac hypertrophy and failure. In Molecular basis of cardiovascular disease. K.R. Chien, editor. W.B. Saunders Co. Philadelphia, Pennsylvania, USA. 211–250.
    1. Blume-Jensen P, Hunter T. Oncogenic kinase signalling. Nature. 2001;411:355–365. - PubMed
    1. Chien KR. Genomic circuits and the integrative biology of cardiac diseases. Nature. 2000;407:227–232. - PubMed
    1. Chien KR. Stress pathways and heart failure. Cell. 1999;98:555–558. - PubMed
    1. Yasukawa H, et al. Suppressor of cytokine signaling-3 is a biomechanical stress–inducible gene that suppresses gp130-mediated cardiac myocyte hypertrophy and survival pathways. J Clin Invest. 2001;108:1459–1467. DOI:10.1172/JCI200113939. - PMC - PubMed

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