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Molecular mechanisms of cardiac hypertrophy induced by toxicants

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Abstract

Cardiac hypertrophy is an end point of chronic cardiac toxicity from a number of toxicants. Doxorubicin, cocaine, acetaldehyde, monocrotaline, and azide are examples of these toxicants, which may induce hypertrophy by increasing oxidants, circulating levels of catecholamines, and hemodynamic load or by inducing hypoxia. We summarize here the major signal transduction pathways and common changes in gene expression found with the classical hypertrophy inducers angiotensin II, endothelin 1, and catecholamines. Activation of G-proteins, calcium signaling, phosphoinositide 3-kinase (PI3K), certain family members of protein kinase Cs (PKCs), and three branches of mitogen-activated protein kinases (MAPKs), i.e. extracellular signal-regulated kinases (ERKs), p38, and c-Jun N-terminal kinases (JNKs), are important for developing a hypertrophic phenotype in cardiomyocytes. Characteristic changes of gene expression in hypertrophy include the elevated transcription of atrial natriuretic factor (ANF), β-myosin heavy chain (βMHC), skeletal α-actin (SkA), certain variants of integrins and perhaps tubulin genes, and reduced expression of the sarcoplasmic reticulum proteins phospholamban and sarco(endo)plasmic reticulum Ca2+-ATPase 2α (SERCA2α), and of the ryanodine receptors. Although which toxicants induce these molecular changes remains to be tested, increasing lines of evidence support that oxidants play a central role in cardiac hypertrophy. Oxidants activate small G-proteins, calcium signaling, P13K, PKCs, and MAPKs. Oxidants cause cardiomyocytes to enlarge in vitro. Recent developments in transgenic, genomic, and proteomic technologies will provide needed tools to reveal the mechanism of chronic cardiac toxicity at the cellular and molecular levels.

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  1. Department of Pharmacology, College of Medicine, University of Arizona, 1501 N. Campbell Ave., 85724, Tucson, AZ

    Qin M. Chen

  2. Interdisciplinary Graduate Program of Pharmacology and Toxicology, College of Medicine, University of Arizona, 1501 N. Campbell Ave., 85724, Tucson, AZ

    Victoria C. Tu, June Wood & Tarrah Dilley

  3. Interdisciplinary Graduate Program of Genetics, College of Medicine, University of Arizona, 1501 N. Campbell Ave., 85724, Tucson, AZ

    Sally Purdom

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Chen, Q.M., Tu, V.C., Purdom, S. et al. Molecular mechanisms of cardiac hypertrophy induced by toxicants. Cardiovasc Toxicol 1, 267–283 (2001). https://doi.org/10.1385/CT:1:4:267

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