Switches in cardiac muscle gene expression as a result of pressure and volume overload KETTY SCHWARTZ, KENNETH R. BOHELER, ANNE-MARIE LOMPRE, AND JEAN-JACQUES Institut National de la Santk et de la Recherche 75010 Paris, France Schwartz, Ketty, Kenneth R. Boheler, Diane de la Bastie, Anne-Marie Lompre, and Jean-Jacques Mercadier. Switches in cardiac musclegeneexpressionasa result of pressureand volume overload. Am. J. Physiol. 262 (Regulatory Integrative Comp. Physiol. 31): R364-R369, 1992.-In the

mammalian heart, the expressionof genesencoding proteins responsiblefor contraction, relaxation, and endocrinefunction changesin hypertrophy resulting from hemodynamicoverload. Different mechanismsare involved in this mechanogenictransduction, including 1) differential expression of myosin and actin multigene families, which may account for the decreased velocity of contractile element shortening in hypertrophied heart, 2) nonactivation of the sarcoplasmicreticulum Ca2+ATPase gene, which may explain the increased duration of isometric relaxation, and finally 3) activation in the ventricle of the atria1 natriuretic factor genethat is responsiblein part for the high plasma levels of this peptide. It is increasingly apparent that these changesare independently regulated, but little is known about the mechanismsunderlying this regulation. Preliminary results indicate that it is now possible to analyze the early time course or transcription for each gene after the imposition of hemodynamic overload. This should significantly enhance our understanding of the regulatory mechanismsinvolved in the phenoconversionsof the hemodynamically overloadedheart. humans and rat; mRNA; myosin heavy chain; actin; sarcoplasmic reticulum Ca’+-ATPase; atria1 natriuretic factor THE IDEA that molecular changes in proteins synthesized by the myocardium may play a major role in the adaptation of the heart to chronic overload, and may influence the long-term prognosis of patients with congestive heart failure, was recognized at a meeting held in Boston in 1987 (45). Since then, it has been striking to see how recombinant DNA technology has accelerated the rate at which we have gained knowledge concerning the mechanisms by which the heart responds to a sustained increase in workload. It is now agreed that pressure and volume overload produce in the myocyte, through a mechanogenic transduction whose pathways are largely unknown, both qualitative changes (i.e., phenoconversions characterized by protein isoform switches) and quantitative changes (characterized by modulation of the expression of individual genes). Our laboratory has been interested in gene regulation in the hypertrophied myocardial cell for several years, and it is the objective of the present paper to review summarily some of the new aspects concerning the molecular basis of changes in cardiac contractility [differential expression of myosin heavy chain (MHC) and actin multigene families], cardiac relaxation (nonactivation of the gene encoding the This paper was presented at the Keystone Conference on Molecular Biology of Muscle Development held in Keystone, CO, January 24-30, 1991.

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Ca2+-ATPase of the sarcoplasmic reticulum), and endocrine function (ventricular activation of the atria1 natriuretic gene) that occur in the hypertrophied and failing heart. Differential Expression of Myosin and Actin Multigene Families Myosin heavy chains. The hexameric myosin molecule consists of two MHCs, two myosin alkali light chains (MLC) and two regulatory myosin light chains (MLC2). The heavy-chain subunits that contain the site for ATPase activity exist in two isoforms, cyand ,& both of which are present in ventricles and atria (for review see Refs. 34 and 45). They are products of two different isogenes that are organized in tandem on the same chromosome: the ,&gene is located 4,000 nucleotides “upstream” of the a-gene (36). The simultaneous presence of two heavychain and four light-chain forms might allow the formation of many different myosin isozymes if all combinations of heavy and light chains were possible. So far, three different myosin isozymes have been characterized in mammalian ventricular muscle V1, V2, and V3 (22). Isozymes V, and V3 are composed of CYCYand ,&?-homodimers, respectively, whereas V2 is an &heterodimer (10, 22). In atria1 muscle, two different forms were also found, A, and A2, which probably correspond to an association of a-type heavy chains with atria1 or ventricular light chains (22, 32). Work overload is accompanied by an induction of ,& MHC with the extent of the isoform change depending on the initial phenotype. In rat ventricular muscle, because of the initial low level of P-MHC (O-10%), the potential for increase is large. ,&MHC accumulates to as much as 80% of total myosin in hypertrophied rat ventricles, and its amount is correlated with the degree of hypertrophy (17, 31, 38). CY-and P-MHCs are expressed in the same myocyte (50,58); however, in the ventricular wall, the expression of each isoform varies from one myocyte to the other, with an increasing gradient for the P-MHC from the epicardium to the endocardium (17). After treatment, the shift is reversible in chronic hypertension (15). In rabbits, the potential for increase is much smaller, since the ventricle of normal young rabbits already contains -5O-60% V3, but the same type of response also occurs with pressure overload (30). Conversely, in pig (59) and human ventricles, which contain mainly V3 (-90%) (5, 18, 39), no marked difference is found during hypertrophy. However, overloaded human ventricular muscle appears to lose the small amount of V1 it normally contains, since this form is not detected either in autopsy material of patients suffering from

0363-6119/92 $2.00 Copyright 0 1992 the American Physiological Society

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hypertensive disease or in perioperative biopsies of patients with valvular heart disease (39). The situation is different in human atria1 muscle, since normal atria1 myocardium (which is characterized by higher contractile performance and higher myosin ATPase activity than the corresponding ventricular muscle) essentially contains cu-MHC linked to atrial-type light chains (5-7, l&40, 56). Chronic hemodynamic overload, whatever its type (mitral stenosis or mitral regurgitation), induces a transition from ar-MHC to ,&MHC, i.e., from an atria1 to a ventricular MHC isoform. The extent of change is correlated with the size of the atrium (Fig. l), suggesting that in human atria, as in rat ventricle, isomyosin transitions are related either to the severity or to the duration of the load or both. A large body of evidence supports the concept that isomyosin shifts are functionally significant in the myocardium. Isozymes V1 and V3 exhibit a difference in their rate of ATP hydrolysis, the calcium-activated and actinactivated ATPase activities of V3 being three- to fivefold lower than those of V1 (22,30, 31). As expected from the close correlation existing between the maximal velocity of contraction of a given skeletal muscle and the ATPase activity of its myosin, a correlation has been demonstrated between the initial speed of muscle shortening at zero load (V,,,) and myosin isotype expression from rat and rabbit heart (16, 29, 47, 52). Moreover, the tensiondependent heat is decreased in pressure-overloaded rabbit hearts (with the V3 myosin isotype), resulting in a greater economy of force development, i.e., a more efficient isometric twitch (1). Thus pressure-overloaded rat and rabbit hearts develop tension more economically than does normal myocardium but at the expense of contractile speed. Actin. Actin is also encoded by a multigene family in mammals. Two sarcomeric actins exist, the a-skeletal and the a-cardiac isoforms (for review see Ref. 34). These isoforms are very similar, and it is difficult to distinguish between them at the protein level. The nucleotide se100 o\” a$ 80

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quences, however, are more divergent, and the 3’ noncoding regions of the mRNAs can be used as gene-specific probes. During the development of cardiac muscle in rodents, mRNA for a-skeletal actin accumulates in fetal and neonatal hearts, and a-cardiac actin mRNA becomes the predominant type in adult hearts (37, 43, 53). We have looked, with the use of two DNA probes corresponding to mouse skeletal and cardiac actin mRNAs, at the accumulation of these mRNAs in pressure-overload hypertrophy of the rat ventricle (53). We found that CYskeletal actin mRNAs are hardly detectable in the normal hearts; they accumulate significantly in the first days after aortic stenosis and then slowly decline. The same observations were made in a similar experimental model using DNA probes corresponding to rat mRNAs (24). Thus, in rat myocardium, the expression of mRNAs encoding the sarcomeric actins is altered significantly only at the onset of a pressure-overload hypertrophy. The functional significance of the different actin isoforms is not known. Two amino acid differences between these isoforms reside in the NH2-terminal peptide that is involved in the interaction with MHC. One might thus postulate that this would result in a fine-tuning of the actomyosin complex. Little is known of the situation in humans, except that both isogenes were found to be coexpressed in three adult ventricular samples (2, 19, 57). We have recently quantified, with a primer extension assay, the true proportion of each mRNA in two hearts, one from an accident victim maintained under intensive care and considered as a control, and one from a patient undergoing cardiac transplantation and suffering from chronic end-stage heart failure (class IV) (4). The ratios of a-skeletal to a-cardiac mRNAs were equal to 0.5 and 1.5 for the control and failing heart, respectively, indicating that, in humans, cyskeletal actin is the major isoform of the cardiac tissue. More sample data are now necessary to determine if this ratio depends on the physiological or pathological condition, but it is clear that the pattern of expression of sarcomeric actins in ventricular muscle is species specific. Independent regulation of MHC and actin multigene families. *Rather strikingly, after imposition of pressure

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Fig. 1. Relation between the indexed left atria1 transverse diameter (LATD) and the associated changes in the proportion of cu-MHC in 34 patients. Patients with the Wolf-Parkinson-White syndrome (0), pure tight mitral stenosis (A, A), mitral stenosis plus mitral regurgitation (v, v), severe mitral regurgitation (0, w), and patients with other types of left atria1 overload (+, 0). Open symbols, subjects with sinus rhythms; closed symbols, subjects with atria1 fibrillation. [From Mercadier et al. (42).]

overload on the rat heart, the time course of upregulation of P-MHC and a-skeletal actin genes is not the same. Whereas the amount of p-MHC mRNA increases in proportion to the extent of hypertrophy and persists as long as the overload is maintained, a-skeletal actin mRNA returns to control values (23, 53). We have investigated by in situ hybridization the distribution of ,& MHC and a-skeletal actin mRNAs during the early stages of cardiac hypertrophy secondary to pressure overload (51). The a-skeletal actin gene is activated earlier than the p-MHC gene, and a-skeletal actin mRNA accumulations are evident throughout the entire left ventricular wall, whereas ,&MHC mRNAs are observed mainly around large coronary arteries and in the inner half of the left ventricular wall (Fig. 2). The difference in the distribution of mRNA accumulations of these two genes argues in favor of independent pathways of activation, suggesting that their regulations are likely to be more complex than was previously

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R366 P--myosin

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Fig. 2. Serial nonconsecutive set tions of rat left ventricles 2 days after ao rtic stenosis, hybridized with fi-MHC and LYskeletal actin riboprobes. [From Schiaftin0 et al. (51).]

thought. With the availability of gene-specific DNA probes, it has been possible to begin to ask at which level the (Y-to P-MHC transition is regulated. In collaboration with the group of Mahdavi (23), we determined protein as well as mRNA levels of expression for cu-MHC and ,& MHC from hypertrophied rat hearts secondary to aortic stenosis. We found that aortic banding results in a rapid induction of the ,&MHC mRNA followed by the appearance of comparable levels of the corresponding protein. This indicates that the MHC isoform transition induced by pressure overload is mainly regulated by pretranslational mechanisms and therefore could comprise transcriptional and posttranscriptional events. Analysis of transcriptional regulation requires the use of in vitro run-on assays with cardiac nuclei isolated from young and adult rats. Because of the inherent difficulties of working with cardiac tissue, only one study had been reported from control rats (35). Very recently we have succeeded in isolating intact nuclei from myocytes of hemodynamically overloaded rat hearts, which have retained their transcriptional capacity (8). Using singlestrand Ml3 probes 50-80 base pairs in length and specific for actin and MHC isogenes, faint but detectable signals were obtained. To enhance and ultimately quantify these signals, intronic probes some 10 times longer than those currently available must be prepared. This should allow precise quantification of the respective transcriptional levels of contractile isogenes and should open new insights into the understanding of the mechanisms that govern gene expressions and thus cardiac structure and function during chronic hemodynamic overload.

Quantitative Changes in Sarcoplasmic Reticulum Ca’+-ATPase and Atria1 Natriuretic Factor Gene Expression Nonactivation of the sarcoplasmic reticulum Ca’+-ATP-

a.segene. Relaxation is modified in the hemodynamically overloaded heart, and until recently the mechanisms responsible for these alterations have been poorly studied. The reduced velocity of lengthening during relaxation of the mechanically overloaded heart is accompanied by abnormal Ca2+ handling and by modifications of the tension-independent heat production, which reflects the energy cost of calcium cycling (for review see Refs. 13 and 34). The role of the sarcoplasmic reticulum (SR) in these alterations had been stressed in many studies conducted on isolated microsomal vesicles. A reduction in the calcium transport by the SR had been observed in experimental compensatory cardiac hypertrophy induced by mechanical overload, and a further decrease in its transport capacity was seen in failing hearts. We observed, in severe hypertrophy of rat left ventricles, a decline in the function of the sarcoplasmic reticulum: the oxalate-stimulated Ca2+ uptake from homogenate of the left ventricular muscle and the number of functionally active Ca2+-ATPase molecules were both decreased (12). To define more precisely which molecular defects are involved, we have cloned a rat cardiac SR Ca2+-ATPase cDNA (33) and looked for the presence of a new isoform of SR Ca’+-ATPase mRNA by S1-nuclease mapping. Fully protected fragments were observed whether the RNA was isolated from normal or pressure-overloaded rat hearts, indicating that the same Ca2+-ATPase mRNA

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is expressed in both normal and hypertrophied cardiac ventricles (12). Similar conclusions were drawn by the team of Yazaki (27) in the same experimental model as ours and by Nagai et al. (46) in right ventricular hypertrophy of the rabbit heart. It should be pointed out that the technique that we and Nagai et al. (46) used (S1nuclease mapping) is extremely sensitive to small structural differences at the mRNA level. Indeed, using this technique we recently detected a different isoform of the Ca2+-ATPase in smooth muscle (11). The expression of the Ca2’-ATPase gene in the overloaded heart has been quantitated by measuring the accumulation of both the mRNA and the corresponding protein. In severe hypertrophy, the concentration of the Ca2+-ATPase mRNA decreased by ~30%, whereas the total amount of mRNA and enzyme per left ventricle was unchanged. This parallel between accumulation of mRNA and protein suggests that as for myosin a pretranslational level of regulation is probably involved. To determine if similar changes occur in human endstage heart failure, we compared the sarcoplasmic reticulum Ca2+-ATPase mRNA levels in left and right ventricular specimens from 13 patients undergoing cardiac transplantation with control heart samples using the same rat probes as above (42). The amount of Ca2+ATPase mRNA was 48 and 47% less in the failing hearts than in the control ones when compared with ribosomal 18s RNA or MHC mRNA, respectively (Fig. 3). Thus, in hemodynamically overloaded hearts, although sarcomeric SR Ca2’-ATPases are encoded by a multigene family, isoform switches analogous to those seen for myosin heavy chain and actin do not occur. The most likely hypothesis for this relative decrease of SR Ca2’ATPase with cardiac hypertrophy is a lack of activation of its gene. This relative decrease may explain some of the modifications of Ca2+ movements and relaxation characteristics that have been described in overloaded cardiac cells. The duration of the intracellular Ca2+ movements, measured using aequorin, are indeed modified in hypertrophied hearts (20, 21). Moreover, chronic congestive heart failure is associated with an inability of the ventricular myocardium to generate sufficient force to ensure normal cardiac output, and it is associated with reduced diastolic relaxation that alters ventricular filling

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and further compromises cardiac function. Possible alterations in SR function that may result from changes in the Ca2+-ATPase mRNA accumulation may be one of the pathophysiological mechanisms responsible for abnormal relaxation and altered contractility due to insufficient activation of myofibrillar proteins during systole. In this respect, the decrease in the ratio of the Ca2+ATPase to the MHC mRNAs suggests that there may be an imbalance in the amount of contraction and relaxation components in the failing myocardium. Ventricular activation of the atria1 natriuretic factor (AM’) gene. ANF, a peptide hormone encoded by a single

gene, is almost exclusively produced by the atria in normal adult hearts. It participates in the short-term regulation of sodium and water balance and therefore in the loading conditions of the cardiac pump. Hemodynamic overload induces in the ventricle a marked expression of the ANF gene. This is true for volume (28) as well as pressure overload in the rat ventricle (9, 41). In the latter, overexpression is biphasic, peaking as cu-skeleta1 actin around day 4 after coarctation of the abdominal aorta (41). It decreases around day 9, increases again, and remains elevated during compensated hypertrophy at almost 10 times its basal level. Overexpression of the ANF gene also occurs in human ventricular muscle during heart failure (49), and increased levels of ANF were found in the anterior interventricular vein (61), indicating that the failing ventricle produces ANF and participates in the increase in the circulating pool of the hormone. The physiological significance of this ventricular recruitment remains unclear since the effects of the hormone appear somewhat blunted, at least at the stage of heart failure. Triggers for Changes in Gene Expression

How can a mechanical event modify gene expression of a cardiac myocyte? There are at least three immediate consequences of a hemodynamic load on the fiber: stretch produced by increased filling of the ventricle and heart vessels (the so-called “erectile effect”), increased wall stress, and finally a thermodynamic disequilibrium inducing most probably mild cellular hypoxia. The effects of stretch and wall stress were clearly demonstrated in vitro on isolated perfused hearts, on well-defined culture n LV systems of neonatal and adult cardiac myocytes and in 1.6 1.6 q RV ferret papillary muscles. Results show that stretch alone can activate protein and RNA synthesis (26), that this effect is more pronounced if the myocytes contract (25), and finally that mechanical activity is necessary, if not obligatory, for myosin and actin synthesis (14). Our findings in vivo of a preferential accumulation of ,&MHC in the myocardial areas where stress and strain are markedly increased (51) (see Fig. 2), as well as the fact that the peak of ventricular ANF mRNA coincides with an elevated left ventricular end-diastolic pressure (4l), strongly support the hypothesis of the major role played HF HF C Fig. 3. Mean values of the sarcoplasmic reticulum (SR) Ca*‘-ATPase/ by stretch. 18s and SR Ca*‘-ATPase/MHC hybridization signals in the left venWhat are the intracellular pathways of this mechanotricles (LV) of control human hearts and in left and right (RV) genie transduction? During the past two or three years, ventricles of patients with end-stage heart failure (HF). Reprinted with permission from the American College of Cardiology (J. Am. CoZZ. at least three possible mechanisms have been described: Cardiol. 9: 1024-1030,1987). elevation of cellular CAMP content (60), stimulation of

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(3,w,

protein kinase C via the al-adrenegic receptor and increased intrace llula r sodium influx via the stretchactivated ion channels (25). More recently, it has been shown that peptide growth factor TGF-fll induces in neonatal cardiac myocytes changes in isomyosins and isoactins resembling those induced by hemodynamic load (48). Interestingly, TGF-P, increases in the surviving and hypertrophied myocytes bordering experimental infarcts (55). Together, these results show the multiplicity of triggers and intracellular pathways that are likely to link the numerous changes in cardiovascular homeostasis observed during diastolic or systolic overload in vivo to the very specific alterations in gene expression observed in the hypertrophied heart.

It is clear that the hemodynamically overloaded hypertrophied heart is more than an enlarged version of the normal heart, as was predicted more than 50 years ago by Louis Katz. Changing the working conditions of the cardiac pump results in a mechanogenic transduction that I.eads to a phenotype resembling that of the fetal heart and tha .t perhaps allo ws the muscle to adapt to the new functional demand. These gene alterations are not specific to a given pathology but most probably represent the response of the myocardium to hemodyna .mic overload. It should be emphasized that normal genes are activ pated or dea ctivated and that the proteins produced have normal structures. Neither the multiple factors involved in this gene reprogramming nor the sequence leading from the mechanical and perhaps also the hormonal triggers of this multifactorial gene modulation are fully understood, and further work is needed to clarify the questions of how hemodynamic stimuli can lead to a new myocardial phenotype. It is likely that an increase in our knowledge of the various triggers and pathways will aid in better understanding the reasons for mechanical dysfunction in the hypertrophied or failing heart and will therefore provide the molecular basis for new curative or preventive therapeutics. REFERENCES Increased myothermal economy of isometric force generation in compensated cardiac hypertrophy induced by pulmonary artery construction in the rabbit. Circ. Res. 50: 491-500, 1982. 2. Bennetts, B. H., L. Burnett, and C. G. DOS Remedios. Differential co-expression of ar-actin genes within the human heart. J. MOL. Cell. CardioZ. 18: 993-996, 1986. 3. Bishopric, N. H., P. C. Simpson, and C. P. Ordhal. Induction of the skeletal ar-actin gene in ai-adrenoreceptor-mediated hypertrophy of rat cardiac myocytes. J. CLin. Inuest. 80: 1194-1199,1987. N. R., and

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cardiac deformation linked to sodium influx. Circ. Res. 64: 74-85, 1989. 26. Kira,

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Altered myosin isozyme patterns from pressure-overloaded and thyrotoxic hypertrophied rabbit hearts. Circ. Res. 50: 846-856, 1982. 31. Lompre, A. M., K. Schwartz, A. D’Albis, G. Lacombe, N. Van Thiem, and B. Swynghedauw. Myosin isoenzyme redistribution in chronic heart overload. Nature Land. 282: 105-107, 1979. 32. Lompre, A. M., B. Nadal-Ginard, and V. Mahdavi. Expres-

sion of the cardiac ventricular cyand ,&myosin heavy chain genes is developmentally and hormonally regulated. J. Biol. Chem. 259: 6437-6446,1984. 33. Lompre, A. M.,

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Characterization and expression of the rat heart sarcoplasmic reticulum Ca2’ ATPase mRNA. FEBS Mt. 249: 35-41, 1989. A. M., J. J. Mercadier, and K. Schwartz. Changes 34. Lompre, in gene expression during cardiac growth. Int. Rev. CytoL. 124: 137186,199O. 35. McCully,

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Boston, MA: International Society for Heart Research and American Heart Association, 8-12 September 1987. 45. Nadal-Ginard, B., and V. Mahdavi. Molecular basis of cardiac performance. Plasticity of the myocardium generated through protein isoform switches. J. Clin. Inuest. 84: 1693-1700, 1989. 46. Nagai, Tada,

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Switches in cardiac muscle gene expression as a result of pressure and volume overload.

In the mammalian heart, the expression of genes encoding proteins responsible for contraction, relaxation, and endocrine function changes in hypertrop...
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