Phenotypic plasticity of adult myocardium: molecular mechanisms

Abstract

Molecular cardiologists, even clinical cardiologists, are familiar with phenotypic plasticity. They call it remodelling*. Myocardial and vascular remodelling have primarily a mechanical origin and an adaptive significance. Cardiac remodelling (CR) occurs in response to chronic mechanical overloading, and arterial remodelling is a response to permanent arterial hypertension (Lompré et al., 1979;Swynghedauw, 1999;Levy and Tedgui, 1999). CR leads to heart failure and, with cancer, is one of the major causes of death in our countries, so cardiac plasticity is a major public health problem. This review will only focus on myocardial remodelling (excluding the remodelling of coronary vessels).This review will start from the most common clinical conditions † , namely CR occurring after myocardial infarction or chronic essential arterial hypertension, and will consider Cardiac phenotypic plasticity (so-called cardiac remodelling, CR) is characterized by changes in myocardial structure that happen in response to either mechanical overload or a loss of substance such as that occurring after myocardial infarction.Mechanosensation is a widespread biological process and is inextricably mixed with other transduction systems from hormones and vasopeptides, which ultimately produce post-translational modifications of transcription factors. The expression of the four main transcription factors during cardiogenesis is also enhanced as a link to foetal reprogramming.CR results from re-expression of the foetal programme, which is mostly adaptive, but also from several other phenotypic modifications that are not usually adaptive, such as fibrosis. (i) The initial determinant is mechanical, and reexpression of the foetal programme includes a global increase in genetic expression with cardiac hypertrophy, reexpression of genes that are normally not expressed in the adult ventricles, repression of genes not expressed during the foetal life, and activation of pre-exisiting stem cells. Microarray technology has revealed a coordinated change in expression of genes pertaining to signal transduction, metabolic function, structure and motility, and cell organism defence. The physiological consequence is a better adapted muscle. (ii) During clinical conditions, the effects of mechanics are modified by several interfering determinants that modify CR, including senescence, obesity, diabetes, ischemia and the neurohormonal reaction. Each of these factors can alter myocardial gene expression and modify molecular remodelling of mechanical origin.Finally, as compared to evolutionary phenotypic plasticity described in plants and insects in response to variations in environmental conditions, in CR, the environmental factor is internal, plasticity is primarily adaptive, and it involves coordinated changes in over 1400 genes. Study of reaction norms showed that the genotypes from different animal species are similarly plastic, but there are transgenic models in which adaptation to mechanics is not caused by hypertrophy but by qualitative changes in gene...

Npr1-regulated gene pathways contributing to cardiac hypertrophy and fibrosis

“…To our knowledge, there have been no other reports in the literature of marked changes in gene expression associated with normal cardiac aging in the absence of pathophysiological changes. However, the phenotypic plasticity of adult myocardium is well documented, associated with the reactivation of the foetal gene programme and the expression of at least four transcription factors, GATA4, MEF2, Csx/Nkx2-5 and e/dHAND (Swynghedauw 2006). This activation is normally attributed to cardiac mechanical overload and wall stress, acting via stretch-activated Ca, K and Na channels and calcineurin (Swynghedauw 2006).…”

“…However, the phenotypic plasticity of adult myocardium is well documented, associated with the reactivation of the foetal gene programme and the expression of at least four transcription factors, GATA4, MEF2, Csx/Nkx2-5 and e/dHAND (Swynghedauw 2006). This activation is normally attributed to cardiac mechanical overload and wall stress, acting via stretch-activated Ca, K and Na channels and calcineurin (Swynghedauw 2006). It may be that arterial stiffness in the aging cardiovascular system leads to increased arterial pre-load, wall stress in the heart and the gradual activation of cardiac transcription.…”

Selective translation of mRNAs in the left ventricular myocardium of the mouse in response to acute pressure overload

“…Hypertrophy of the myocardium is produced by a global increase in protein synthesis that facilitates accumulation of myofibrils, mitochondria and other primary components of the cardiac muscle cell (cardiocyte) [3,4]. Translational mechanisms play a major role in accelerating the rate of protein synthesis in response to pressure overload by increasing the activity (efficiency) and amount (capacity) of the translation machinery, i.e., ribosomes and associated components such as eukaryotic initiation factors (eIFs) [5,6].…”

“…In addition to increased protein content, the hypertrophic phenotype is generated by selective changes in gene expression that regulate growth and modify the structural and functional properties of the cardiocyte [4]. Transcriptional mechanisms are postulated to direct these changes, thereby producing the hypertrophic gene program that is essential for the development of compensatory growth [8].…”

Myocardial remodeling, an overview

“…-The inadequate increase in capillary density of the hypertrophying and remodeling myocardium that results in inadequate oxygenation [12]. Indeed, even after an acute myocardial infarction, capillary density is decreased as REM ensues [13] As already mentioned, a main characteristic of the remodeling myocardium is the return to the ''fetal'' phenotype, which is characterized by decreased contractility but also lower energy consumption [14]. Also, the ratio HMC a/b is decreased, ANP and BNP and a-actin overexpressed, and the SERCA/phospholamban activity decreased.…”