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Cardiac Remodeling in the Hypertrophic Heart: Signal-Dependent Regulation of the Fibrotic Gene Program by CLP-1

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Cardiac Adaptations

Part of the book series: Advances in Biochemistry in Health and Disease ((ABHD,volume 4))

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Abstract

The response of the heart to hypertrophic stress stimuli is designed to normalize heart function under conditions of increased demand. To achieve this, the heart must mount a genomic stress response that is itself responsive to the signal transduction pathways used by heart cells to transmit stress signals. The ability to adaptively link stress signal to genomic stress response is critical to how the heart responds to stress. Our laboratory has been studying the molecular events involved in this adaptive linkage. Our studies have shown that CLP-1 (Cardiac Lineage Protein-1), the mouse homolog of the human HEXIM1, acts as the molecular “go-between” linking stress signal with genomic stress response. Critical to this linkage is HEXIM1/CLP-1’s control of cyclin-dependent kinase 9 (cdk9), the kinase responsible for activating RNA polymerase (pol) II to complete synthesis of nascent stress gene transcripts. Through its control of cdk9, HEXIM1/CLP-1 controls the transcriptional output of stress response genes by regulating the ability of RNA polymerase (pol) II, and as more recent data has shown, the activity of specific transcription factors such as those of the small mother against decapentaplegic(smad) family, to transcribe stress response genes. Together, these observations provide strong support for the idea that HEXIM1/CLP-1 plays a critical role in controlling the response of cardiac cells to hypertrophic stress stimuli.

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Abbreviations

CLP-1:

Cardiac lineage protein-1

HEXIM1:

Hexamethylene bis-acetamide-inducible protein 1

Cdk9:

Cyclin-dependent kinase 9

P-TEFb:

Positive transcription elongation factor b

Smad:

Small mother against decapentaplegic

Ang II:

Angiotensin II

SHR:

Spontaneously hypertensive rat

MAP kinase:

Mitogen-activated protein kinase

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Authors and Affiliations

  1. The Center for Cardiovascular and Muscle Research and Department of Cell Biology, State University of New York Downstate Medical Center, 450 Clarkson Avenue, New York, 11203, USA

    Michael Wagner & M. A. Q. Siddiqui

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  1. Michael Wagner
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  2. M. A. Q. Siddiqui
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Correspondence to M. A. Q. Siddiqui .

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Editors and Affiliations

  1. Czech Republic, Institute of Physiology, Academy of Sciences of the, Videnska 1083, Prague, 142 20, Czech Republic

    Bohuslav Ostadal

  2. St. Boniface General Hospital, Research Centre, Institute of Cardiovascular Sciences, Tache Avenue 351, Winnipeg, R2H 2A6, Manitoba, Canada

    Naranjan S. Dhalla

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Wagner, M., Siddiqui, M.A.Q. (2013). Cardiac Remodeling in the Hypertrophic Heart: Signal-Dependent Regulation of the Fibrotic Gene Program by CLP-1. In: Ostadal, B., Dhalla, N. (eds) Cardiac Adaptations. Advances in Biochemistry in Health and Disease, vol 4. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-5203-4_18

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