Genetic modification of the heart

Chaperones and the cytoskeleton

Asangi R.K. Kumarapeli, Xuejun Wang

Research output: Contribution to journalReview article

56 Citations (Scopus)

Abstract

In the past decade, genetic modification has been extensively employed to define (patho)physiological roles of chaperones and the cytoskeleton in the heart, promoting dramatic advances in this field. Both loss-of-function and gain-of-function approaches have been used productively. αB-Crystallin (CryAB) is the most abundant small heat shock protein (HSP) in the heart. A missense mutation (R120G) in CryAB that is linked to human desmin-related myopathy (DRM), has proved in transgenic (TG) mice to be causative, likely through compromising the function of both CryAB and desmin filaments and inducing aberrant protein aggregation. For the molecular chaperones, the consensus gained is that up-regulation of each of the HSPs in the heart is protective against insults such as ischemia/reperfusion (I/R) injury. CryAB modulates protein aggregation of abnormal desmin. With respect to the cytoskeleton, disruption of the non-sarcomeric actin linkage at the intercalated discs via overexpressing the VASP-EHV1 domain is sufficient to cause dilated cardiomyopathy (DCM). Up-regulation of microtubule-associated protein 4 (MAP4) results in microtubule densification. Myocyte contractile malfunction characteristic of pressure overload hypertrophy is recapitulated by cardiac-restricted overexpression of MAP4. In contrast, overexpression of desmin filaments by itself is not detrimental to the heart. Although loss-of-function studies have been more limited, ablation of the desmin gene causes mitochondrial dysfunction and apoptosis, resulting in cardiomyopathy in mice. From function studies, abnormal desmin aggregation and disruption of the desmin networks resulting from expression of either mutant desmin or mutant CryAB have been shown to remodel the heart and compromise cardiac function, suggesting their synergistic roles in disease pathogenesis.

Original languageEnglish (US)
Pages (from-to)1097-1109
Number of pages13
JournalJournal of Molecular and Cellular Cardiology
Volume37
Issue number6
DOIs
StatePublished - Jan 1 2004

Fingerprint

Desmin
Cytoskeleton
Up-Regulation
Small Heat-Shock Proteins
Crystallins
Molecular Chaperones
Mitochondrial Genes
Dilated Cardiomyopathy
Missense Mutation
Reperfusion Injury
Cardiomyopathies
Microtubules
Muscle Cells
Hypertrophy
Transgenic Mice
Actins
Proteins
Apoptosis
Pressure

Keywords

  • Desmin
  • Desmin-related cardiomyopathy
  • Heat shock proteins
  • Intermediate filaments
  • Microtubules
  • Protein aggregation
  • αB-crystallin

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

Cite this

Genetic modification of the heart : Chaperones and the cytoskeleton. / Kumarapeli, Asangi R.K.; Wang, Xuejun.

In: Journal of Molecular and Cellular Cardiology, Vol. 37, No. 6, 01.01.2004, p. 1097-1109.

Research output: Contribution to journalReview article

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