The vascular smooth muscle alpha-actin gene is reactivated during cardiac hypertrophy provoked by load.

Abstract

Cardiac hypertrophy triggered by mechanical load possesses features in common with growth factor signal transduction. A hemodynamic load provokes rapid expression of the growth factor-inducible nuclear oncogene, c-fos, and certain peptide growth factors specifically stimulate the "fetal" cardiac genes associated with hypertrophy, even in the absence of load. These include the gene encoding vascular smooth muscle a-actin, the earliest a-actin expressed during cardiac myogenesis; however, it is not known whether reactivation of the smooth muscle a-actin gene occurs in ventricular hypertrophy. We therefore investigated myocardial expression of the smooth muscle a-actin gene after hemodynamic overload. Smooth muscle a-actin mRNA was discernible 24 h after coarctation and was persistently expressed for up to 30 d. In hypertrophied hearts, the prevalence of smooth muscle a-actin gene induction was 0.909, versus 0.545 for skeletal muscle a-actin (P < 0.05). Ventricular mass after 2 d or more of aortic constriction was more highly correlated with smooth muscle a-actin gene activation (r = 0.852; P = 0.0001) than with skeletal muscle a-actin (r = 0.532; P = 0.009); P < 0.0005 for the difference in the correlation coefficients. Thus, smooth muscle a-actin is a molecular marker of the presence and extent of pressure-overload hypertrophy, whose correlation with cardiac growth at least equals that of skeletal a-actin. Induction of smooth muscle a-actin was delayed and sustained after aortic constriction, whereas the nuclear oncogenes c-jun and junB were expressed rapidly and transiently, providing potential dimerization partners for transcriptional control by c-fos. (J. Clin. Invest. 1991. 88:1581-1588

Myocardin-Related Transcription Factor A Is a Common Mediator of Mechanical Stress- and Neurohumoral Stimulation-Induced Cardiac Hypertrophic Signaling Leading to Activation of Brain Natriuretic Peptide Gene Expression

“…Mechanical stress is one of the earliest stimuli promoting the induction of cardiac hypertrophy, which is characterized in part by reactivation of the fetal cardiac gene program (e.g., ANP, BNP, skeletal ␣-actin, ␤-myosin heavy chain, SM22␣, and smooth muscle ␣-actin) (4,15,25). Using an in vitro cardiac myocyte model, it has been shown that mechanical stretch activates a variety of intracellular signaling molecules, including PKC, MAPKs, p90 and p70 S6 kinases, Jak-STAT, and Rho family small G proteins (1,16,27,47,48,51,62).…”

“…Hemodynamic overload, a combination of mechanical stress and neurohumoral stimulation, induces a hypertrophic response characterized in part by reactivation of the fetal gene program in cardiac myocytes (4,15,25,45,58). Though cardiac hypertrophy initially serves as an adaptive response to increased cardiac output, when sustained it leads to cardiac decompensation and heart failure, which is now a leading cause of morbidity and mortality around the world.…”

Transcriptional Regulation of the Fetal Cardiac Gene Program

“…SMA is also expressed in the fetal heart, but its expression declines during the final step in cardiac development and is completely absent from mature cardiac myocytes (42,43). Ventricular SMA gene expression is re-induced in response to hypertrophic stimuli (3,44), and the promoter-enhancer region extending from −2560 bp through the first intron (+2784 bp) of the SMA gene is sufficient to recapitulate the expression pattern of the endogenous SMA gene (45). This region contains three conserved CArG elements, a transforming growth factor β1 control element (TCE, a potential KLF family transcription factors-binding site), two E-boxes, and two MCAT elements (46).…”

“…Genes within this group include atrial and brain natriuretic peptide (ANP and BNP, respectively), fetal isoforms of contractile proteins (skeletal α-actin and β-myosin heavy chain), fetal type cardiac ion channels (hyperpolarizationactivated cyclic nucleotide-gated channel and T-type Ca 2+ channel) and some smooth muscle genes (smooth muscle α-actin and SM22α). All of these genes are abundantly expressed in fetal ventricles but are silent after birth (1,3,4). However, their expression is re-induced when the heart comes under pathological stress, and this expression is thought to play a key role in the molecular process underlying pathological cardiac remodeling (5).…”

Insulin-like growth factor-I stimulates myofibrillar genes and modulates atrial natriuretic factor mRNA in rat heart

“…During overload-induced cardiac hypertrophy, ventricular heart cells re-express foetal gene products such as skeletal a-actin, smooth muscle a-actin and atrial natriuretic factor (ANF) and switch from the a-to the b-myosin heavy chain (MHC) as the main isoform (1)(2)(3)(4)(5). Several pieces of evidence point to a specific role of insulin-like growth factor-I (IGF-I) and growth hormone (GH) in cardiomyocyte plasticity.…”