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[Plasticity of myocardial phenotype during cardiac hypertrophy and failure]
J J Mercadier1, A M Lompre, B Swynghedauw
1Département de recherche médicale, CNRS URA 1159, hôpital Marie Lannelongue, Le Plessis Robinson.
Insights
Cardiac hypertrophy and failure involve significant gene expression changes, altering heart muscle contraction and relaxation. Understanding these molecular shifts is key to addressing cardiovascular disease complications.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Gene Expression Regulation
Context:
- Cardiac hypertrophy and failure are common complications in cardiovascular diseases.
- These conditions involve significant changes in the heart's contractile and endocrine functions.
- Chronic hemodynamic overload drives alterations in gene expression within the myocardium.
Purpose:
- To explore the molecular mechanisms underlying cardiac hypertrophy and failure.
- To identify changes in gene expression related to myocardial function.
- To understand the role of specific proteins and genes in cardiac remodeling.
Summary:
- Differential expression of myosin heavy chain isoforms (alpha vs. beta) affects myocardial contraction efficiency.
- Changes in actin isoform expression (alpha-skeletal actin) occur during overload and heart failure.
- Reduced sarcoplasmic reticulum Ca(2+)-ATPase expression impacts cardiac relaxation.
- Activation of the atrial natriuretic factor gene in the ventricle aids in regulating loading conditions.
Impact:
- Elucidates the molecular basis of altered cardiac function in disease states.
- Highlights potential therapeutic targets for managing cardiac hypertrophy and failure.
- Provides insights into the complex gene reprogramming that occurs in the failing heart.
Abstract:
Cardiac hypertrophy and failure frequently cause complications in some cardiovascular diseases. Both conditions are associated with important modifications of the heart's contractile and endocrine functions, induced by various changes in gene expression, which in turn are attributable to chronic hemodynamic overload. Differential expression of the myosin heavy chain family leads to a disproportionate accumulation of the alpha form relative to the beta, which in turn causes slower but more efficient myocardial contraction. This transition occurs in the rodent ventricle and human atrium. In the sarcomeric actin family, both the alpha-cardiac and alpha-skeletal isoforms are expressed in the mammalian ventricle in utero. After birth, the latter transiently accumulates in the rodent ventricle at the acute phase of an experimental overload. In humans, alpha-skeletal actin accounts for over half of total actin; this ratio remains the same during heart failure. In experimental models of hemodynamic overload, and during heart failure in humans, expression of Ca(2+)-ATPase in the sarcoplasmic reticulum is reduced. This decrease may partly account for the changes in cardiac relaxation observed in these circumstances. The atrial natriuretic factor gene in the ventricular myocardium is also activated, permitting the ventricle to participate in the regulation of its loading conditions. Several mechanical and neurohumoral factors have been proposed as triggers for this gene reprogramming. Research is currently focussed on signal transduction mechanisms, and in particular identification of the transcription factors involved.