New Molecular Mechanisms for Cardiovascular Disease: Transcriptional Pathways and Novel Therapeutic Targets in Heart Failure
Autor: | Koichiro Kuwahara, Kazuwa Nakao |
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Rok vydání: | 2011 |
Předmět: |
medicine.medical_specialty
Biology TRPC6 Transient receptor potential channel Internal medicine Serum response factor medicine Transcriptional regulation Animals Humans Gene Regulatory Networks TRPC Heart Failure Pharmacology lcsh:RM1-950 NFAT medicine.disease Cell biology lcsh:Therapeutics. Pharmacology Endocrinology Cardiovascular Diseases Heart failure cardiovascular system Molecular Medicine Signal transduction Signal Transduction |
Zdroj: | Journal of Pharmacological Sciences, Vol 116, Iss 4, Pp 337-342 (2011) |
ISSN: | 1347-8648 1347-8613 |
Popis: | Genetic remodeling contributes to the progression of heart failure by affecting myocardial cellular function and survival. In our investigation of the transcriptional regulation of cardiac gene expression, we found several transcriptional pathways involved in pathological cardiac remodeling. A transcriptional repressor, neuron-restrictive silencer factor (NRSF), regulates expression of multiple fetal cardiac genes through the activity of histone deacetylases (HDACs). Inhibition of NRSF in the heart results in cardiac dysfunction and sudden arrhythmic death accompanied by re-expression of a number of fetal genes, including those encoding fetal ion channels, such as the T-type Ca2+ channel. In the pathological calcineurin – nuclear factor of activated T-cells (NFAT) signaling pathway, transient receptor potential cation channel, subfamily C, member 6 (TRPC6) is a key component of a Ca2+-dependent regulatory loop. Indeed, inhibition of TRPC significantly ameliorates this pathological process in a mouse model of cardiac hypertrophy. Moreover, we recently showed that myocardin-related transcription factor-A (MRTF-A), a coactivator of serum response factor (SRF), mediates prohypertrophic signaling by linking the small GTPase Rho-actin dynamics signaling pathway to cardiac gene transcription. Collectively, our studies have revealed the transcriptional network involved in the development of cardiac dysfunction and potential therapeutic targets for the treatment of heart failure. Keywords:: neuron-restrictive silencer factor (NRSF), myocardin-related transcription factor-A (MRTF-A), transient receptor potential cation channel, heart failure, cardiovascular disease |
Databáze: | OpenAIRE |
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