(Hypertension. 1997;29:15.)
© 1997 American Heart Association, Inc.
Research Articles (Issue 1, Part 1) |
Senescent Heart Compared With Pressure Overload–Induced Hypertrophy
the Institut National de la Santé et de la Recherche Médicale (INSERM) U127, IFR Circulation, Hôpital Lariboisière, Paris (P.A., D.C., B.S.); Service de Cardiologie, Hôpital Bichat-Claude Bernard, Paris (P.A., P.-E.V.); Faculté de Pharmacie Université Aix-Marseille II, Marseille (S.L.); and Laboratoire de Physiopathologie Cellulaire Cardiaque, ESA CNRS 5077 (J. de L., F.B., S.B.), Université Joseph Fourier, Grenoble, France.
Correspondence to Dr Sophie Besse, Laboratoire de Physiopathologie Cellulaire Cardiaque, ESA CNRS 5077, 2280 rue de la Piscine, Université Joseph Fourier, BP 53X, 38041 Grenoble Cedex, France.
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Abstract |
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Although systolic left ventricular (LV) function is normal in the elderly, aging is associated in rat papillary muscle with mechanical and sarcoplasmic reticulum Ca2+ ATPase alterations similar to those observed in the hypertrophied heart. However, alterations in the other calcium-regulating proteins implicated in contraction and relaxation are still unknown. To investigate alterations in LV function and calcium-regulating proteins, we measured hemodynamics and Na+-Ca2+ exchanger (NCx), ryanodine receptor (RyR2), and sarcoplasmic reticular Ca2+ ATPase (SERCA2) mRNA levels (expressed in densitometric scores normalized to that of poly(A+) mRNA) in left ventricle from 4-month-old (adult, n=13) and 24-month-old (senescent, n=15) rats. For ex vivo contractile function, active tension was measured during isolated heart perfusion in adult (n=11) and senescent (n=11) rats. For comparison of age-dependent effects of moderate hypertension on both hemodynamics and calcium proteins, renovascular hypertension was induced or a sham operation performed at 2 (n=11 and n=6) and 22 (n=26 and n=5) months of age. In senescent rats, LV systolic pressure and maximal rates of pressure development were unaltered, although active tension was depressed (4.7±0.4 versus 8.3±0.7 g/g heart weight in adults, P<.0001). SERCA2 mRNA levels were decreased in senescent left ventricle (0.98±0.05 versus 1.18±0.05 in adults, P<.01), without changes in NCx and RyR2 mRNA accumulation. Renovascular hypertension resulted in 100% mortality in aged rats; in adults, renovascular hypertension resulted, 2 months later, in an increase of LV systolic pressure (170±7 versus 145±3 mm Hg in sham-operated rats, P<.05) and in mild LV hypertrophy (+18%, P<.01) associated with a decrease in SERCA2 mRNA levels (1.02±0.03 versus 1.18±0.03 in sham-operated rats, P<.001). Contractile dysfunction in senescent isolated heart and decreased SERCA2 mRNA levels were associated with in vivo normal LV function at rest, indicating the existence of in vivo compensatory mechanisms. RyR2 and NCx gene expressions were not implicated in the observed contractile dysfunction. In aged rats, renovascular hypertension resulted in 100% mortality, probably related to elevated levels of circulating angiotensin II, whereas in adult rats, renovascular hypertension induced a mild LV hypertrophy associated with a selective alteration in SERCA2 gene expression.
Key Words: aging • antiporters, sodium-calcium • Ca2+-transporting ATPase • ryanodine • hemodynamics • heart
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Introduction |
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Myocardial function in senescence is a controversial issue. Studies in humans, such as the Baltimore study, have demonstrated that both cardiac output, at rest and during exercise, and ejection fraction were unaltered during aging1 despite pronounced and well-documented alterations of LV filling and diastolic compliance.2 In contrast, numerous works in several rat species using isolated hearts3 4 and papillary muscles5 6 7 have indicated major alterations not only in resting tension and tissue stiffness but in contraction and active relaxation. Such a discrepancy between in vivo and ex vivo data suggests the existence of efficient adaptational mechanisms that allow the preservation of cardiac function despite depressed contractility. One of the goals of the present work was to find evidence for such compensatory mechanisms by comparing in vivo and ex vivo ventricular function in senescent rats.
In both senescent and pressure-overloaded rat hearts, the decrease in contractile velocity observed in vitro is commonly attributed to an isomyosin shift that causes changes in myosin ATPase activity,8 9 10 while the main determinant of the diminution of the relaxation velocity should be a decreased density in SR Ca2+ ATPase.7 11 12 However, this view, which is based on correlation studies, is not complete. Indeed, both shortening velocity and active relaxation depend on the availability of intracellular calcium, and obviously, other membrane proteins are involved in the calcium movements, including the NCx and calcium-release channel, also called the ryanodine receptor. Few data are currently available concerning these two major proteins in senescent13 and overloaded14 15 hearts, especially at the molecular level.16 17 The second goal of the present work was therefore to complete our information on these calcium proteins, which are potentially implicated in contractile alteration of both senescent and overloaded hearts, and to determine the relative roles of these three important determinants of calcium movement.
As initially suggested by Lakatta,6 the senescent heart resembles a pressure-overloaded hypertrophied heart in many ways, except in terms of fibrosis.18 Indeed, it has been repeatedly suggested19 that during aging, the heart is progressively submitted to a slight degree of LV overload caused by enhanced aortic impedance.2 The third goal of this work was to compare the senescent heart with a model of compensatory hypertrophy caused by a moderate pressure overload in terms of LV function and calcium-regulating proteins.
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Methods |
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Experimental Protocol
Male Wistar rats (2, 4, 22, and 24 months old) were obtained from Iffa Credo (Lyon, France) and fed ad libitum. The mortality rate at 24 months of age in this population is 50%.
Four-month-old (adult) and 24-month-old (senescent) rats were randomly divided into four experimental groups (groups 1 through 4). Groups 1 (4-month-old rats, n=13) and 2 (24-month-old rats, n=15) were subjected to in vivo hemodynamic measurements under anesthesia followed by euthanasia for RNA extraction and quantification. In groups 3 (4-month-old rats, n=11) and 4 (24-month-old rats, n=11), the hearts were isolated and perfused according to Langendorff20 for ex vivo measurements of myocardial function.
Two- and 22-month-old rats were also randomly divided into four groups (groups 5 through 8). Groups 5 (2-month-old rats, n=11) and 6 (22-month-old rats, n=26) were submitted to renovascular hypertension obtained by placement of a partially occluded Weck hemoclip (0.25-mm diameter) around the left kidney artery (two-kidney, one clip Goldblatt model).21 Groups 7 (2-month-old rats, n=6) and 8 (22-month-old rats, n=5) were subjected to the same procedure without placement of the clip (sham operation). Two months later, the surviving rats were submitted to in vivo hemodynamic measurements under anesthesia and euthanized for RNA extraction and molecular biological studies. Therefore, in our experimental protocol, in vivo hemodynamics and molecular biological studies were performed on the same rats (groups 1, 2, 5, 7, and 8), but ex vivo studies on isolated hearts were done on different groups (groups 3 and 4).
Surgical procedures, hemodynamics, and heart excision were performed with rats under anesthesia by intraperitoneal injection of thiopental sodium (Nesdonal, Specia, Rhône-Poulenc Rorer) at 50 and 30 mg/kg in 4- and 24-month-old rats, respectively. All animal procedures were in accordance with institutional guidelines and the guidelines formulated by the European Community for use of experimental animals (L358-86/609/EEC).
Hemodynamic Measurements
Functional parameters were measured in closed-chest anesthetized rats. After tracheotomy, a cannula was placed in the trachea through which the rats breathed spontaneously. Aortic and ventricular systolic pressures, ventricular diastolic pressures, and maximal rates of ventricular pressure development were measured with an ultraminiature catheter pressure transducer (model PR-249, Millar Instruments, Inc). For LV catheterization, the catheter was inserted into the right carotid artery and advanced upstream from the aorta to the left ventricle. The ultraminiature catheter pressure transducer was attached to a transducer control unit (model TC100, Millar Instruments, Inc) that was connected to a recorder (2000 series, Gould Electronic). The first derivatives for the maximal rate of LV pressure development (+LVdP/dt) and maximal rate of relaxation (-LVdP/dt) were obtained electronically by means of a differentiator (Gould). After LV catheterization, hearts were excised and weighed. The left ventricle with septum and right ventricle were separated, blotted, weighed, frozen rapidly in liquid nitrogen, and stored at -80°C until use for RNA isolation.
Isolated Heart Perfusion
After anesthesia, the heart was rapidly excised and perfused according to the Langendorff method20 at a perfusion pressure of 75 mm Hg. The perfusate was a Krebs-Henseleit solution containing (mmol/L) NaCl 118, NaHCO3 25, KCl 4.8, KH2PO4 1.2, MgCl2 1.2, CaCl2 1.2, and glucose 11 (pH 7.4, 37°C) and was bubbled constantly with 95% O2/5% CO2. The range of oxygen partial pressure, measured at the level of the aortic cannula, was 620 to 680 mm Hg. The heart was paced at a rate of 240 beats per minute at 200% of threshold with a 2-millisecond stimulation duration with an SD9 stimulator (Grass Instrument Co). Active and resting developed tensions were recorded by a hook attached to a force transducer (type 351, Hugo Sachs Electronik) connected to a Gould recorder (2000 model). The +dT/dt and -dT/dt values were obtained electronically by means of a Gould differentiator. We have chosen to measure myocardial contractile force by a hook attached to the apex of the heart rather than an intraventricular balloon because the balloon creates a pressure gradient among the ventricular wall that could modify the perfusion gradient between epicardial and endocardial layers.
For each heart, active and resting developed tensions, both +dT/dt and -dT/dt, and coronary flow at a perfusion pressure of 75 mm Hg were measured after 15 minutes of equilibration. After perfusion, hearts were weighed to normalize the measurements.
RNA Isolation and Analysis
Total RNA was isolated according to Chomczynski and Sacchi22 from individual left ventricles rather than from isolated myocytes because during cardiocyte purification, different subpopulations of cells may be selected, depending on the pathological conditions.
For Northern blot analysis, 20 µg total RNA was denatured in 50% formamide, 2.2 mol/L formaldehyde, and 1x 3-(N-morpholino)propanesulfonic acid (MOPS) buffer (pH 8.0); size-fractionated on 1% agarose gels; and transferred to a nylon Hybond N membrane (Amersham). For slot blot analysis, denatured total RNAs (1, 2.5, 5, 10, and 15 µg) were applied directly to nylon Hybond N membranes. All blots underwent ultraviolet irradiation to covalently link the RNA samples.
Northern and slot blots containing RNA samples from the left ventricles of both 4- and 24-month-old rats were sequentially hybridized with the following probes: a rat cardiac NCx cDNA probe (580 bp) (gift from K. Boheler), a rat cardiac RyR2 cDNA probe (541 bp) (kind gift from Anne Marie Lompré), a rat cardiac SERCA2 cDNA probe (507 bp) (kind gift from Anne Marie Lompré), a 25- to 30-mer oligo(dT) (Pharmacia), and a 24-mer oligonucleotide complementary to nucleotides 1046 to 1070 of the rat 18S rRNA (Institut Pasteur, Paris, France). The two last probes were used to normalize the measurements. The cDNA probes were labeled by random priming with [
-32P]dCTP with a Rediprime Kit (Amersham) and the synthetic oligonucleotide with T4 polynucleotide kinase (Boehringer Mannheim) and [
-32P]ATP.
Prehybridization and hybridization for NCx, RyR2, and SERCA2 probes were performed in 50% formamide, 5x Denhardt's solution, 5x SSPE (standard saline phosphate and EDTA), 0.1% sodium dodecyl sulfate (SDS), 200 µg/mL herring sperm DNA, and 20 µg/mL poly(A+) at 42°C. Washing conditions were as follows: (1) NCx probe: washed in 0.5x SSC/0.1% SDS at 45°C; and (2) RyR2 and SERCA2 probes: washed in 0.5x SSC/0.1% SDS at 50°C. The specificity of these probes was previously reported.17 23 24 Hybridization conditions and washes used for the oligo(dT) and 18S RNA probes were previously described.7
Northern blots were used to test the specificity of each probe and were exposed to x-ray films (Hyperfilm, Amersham) with Quanta III intensifying screens for 16 hours to 8 days at -70°C. Slot blots were used to quantify mRNA levels and were exposed in intensifying screens (Fuji imaging plate type BAS IIIS, Fuji Co) and then analyzed in a Bioimaging analyzer (BAS 1000 Mac BAS, Fuji Co). The relative level of each mRNA species was determined on slot blots by scanning densitometry (Mac BAS software 1.01, Fuji Co), and the densitometric scores of each specific mRNA were normalized for poly(A+) mRNA and 18S rRNA.
Statistical Analysis
Values are expressed as mean±SE. The statistical significance of differences among the various groups was determined by one-way ANOVA, and group-to-group comparisons were made by two-tailed unpaired Student's t test. A value of P<.05 was considered to be statistically significant.
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Results |
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Anatomic and Hemodynamic Studies
Senescent rats (group 2) had significantly higher body weights and heart weights than 4-month-old rats (group 1) (Table 1). However, the ratio of LV weight to right ventricular weight, an index of LVH that is independent of body weight, was unchanged with aging.
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Aortic systolic and diastolic pressures, LV systolic and diastolic pressures, and both +LVdP/dt and -LVdP/dt were the same at 4 (group 1) and 24 (group 2) months of age. Senescence slightly decreased heart rate (Table 1).
Clipping of the left kidney artery induced 100% mortality within 4 to 14 days after surgery in the 22-month-old rats (group 6). Autopsy did not indicate hemorrhage in the area of the renal artery clipping or visible alterations of other organs, such as the liver, right kidney, digestive tract, heart, or lung. The mortality rate was 20% in the senescent sham-operated rats (group 8). In 2-month-old rats, the mortality rate was 0% in both the renovascular hypertensive group (group 5) and sham-operated rats (group 7). Such an intervention induced, within 8 weeks, a modest systolic and diastolic arterial hypertension and a mild LVH, with elevation of the ratio of LV weight to right ventricular weight (+18%, P<.01) and without any significant changes in body weight, heart weight, LV weight, and right ventricular weight (Table 2). LV diastolic pressure, +LVdP/dt and -LVdP/dt, and heart rate were unmodified (Table 2).
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Isolated Heart Studies
Coronary flow, measured at a constant pressure of 75 mm Hg after equilibration, was diminished in senescent rat hearts (group 4: 6.46±0.26 mL/min per gram heart weight) compared with hearts of young adult rats (group 3: 7.72±0.37, P<.05). Similarly, active tension and both +dT/dt and -dT/dt were markedly decreased in senescent myocardium (Table 3). Resting tension was adjusted by hook traction in each heart to produce maximal developed tension. Resting tension was lower in senescent myocardium, indicating that the senescent hearts were stiffer than the young ones (Table 3).
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Quantification of Calcium-Regulating Protein mRNAs
In the left ventricle of 24-month-old rats (group 2), the ratio of SERCA2 to poly(A+) mRNA was diminished compared with that in 4-month-old rats (group 1), without any alterations in the ratios of RyR2 to poly(A+) mRNA and NCx to poly(A+) mRNA (Figs 1 and 2). Similar results were obtained when the mRNA levels were normalized with the 18S rRNA (Table 4).
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The same pattern of results was also obtained in the 4-month-old Goldblatt rats (group 5). The ratios of SERCA2 to poly(A+) or SERCA2 to 18S RNA were decreased (Figs 3 and 4, Table 4), and no significant changes were observed in the ratios of RyR2 to poly(A+) or RyR2 to 18S RNA and NCx to poly(A+) or NCx to 18S RNA compared with sham-operated rats (group 7).
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Discussion |
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The main findings of this study were the following: (1) The contractility of isolated senescent heart is depressed in contrast to LV function in the entire animal, suggesting the existence of peripheral adaptational mechanisms that compensate in vivo for the alterations observed ex vivo. (2) In adult rats submitted to a moderate degree of pressure overload, SR Ca2+ ATPase, one of the main determinants of relaxation, is the first impaired calcium handling system, which corresponds to well-known clinical features. (3) Senescence, as well as renovascular hypertension, is associated with a decrease in SR Ca2+ ATPase mRNA without any alterations of the RyR2 or NCx transcripts, suggesting that the aged heart is comparable to pressure overload in the first stage of LVH. (4) Renovascular hypertension is not tolerated by aged rats, as all died a few days after the surgical procedure, in contrast to other models of mechanical overload such as deoxycorticosterone acetate–salt or aortic stenosis, suggesting that the aging heart has a particular sensitivity to elevated plasma Ang II.
Compensatory Mechanisms in Senescence
The present data on isolated heart confirm those previously published on the papillary muscle.7 In senescence, on the Langendorff preparation perfused at constant perfusion pressure, active and resting tensions and both +dT/dt and -dT/dt were altered by aging, as were the maximal unloaded shortening and relengthening velocities and the active and resting tensions on the papillary muscle. In addition, the coronary circulation was impaired since coronary flow was reduced in senescent myocardium. Similar results were previously observed in other rat strains.4 25 26
Several factors may contribute specifically to senescent myocardial dysfunction, including myocyte cell loss,27 inadequate myocardial perfusion with reduced coronary reserve,26 and arrhythmias.28 Fibrosis is obviously a major factor to explain this myocardial dysfunction because the myocardial collagen concentration increases linearly with aging, in rats as well as in humans, and 24-month-old rat hearts are extremely fibrotic.18 However, the deleterious aspects of the phenotypic adaptational process could also play a role, including the isomyosin shift and the multiple changes in the expression of the genes encoding the calcium-regulating proteins, resulting in an enhanced sensitivity to calcium overload.29
However, in sharp contrast, our in vivo study indicates that Wistar senescent rats had normal LV hemodynamic parameters. Similar results have been reported in humans1 30 as in other rat strains,27 31 including Fischer 344 rats at 20 but not at 29 months of age, in which a decrease in the hemodynamic performance of the left ventricle was observed.32 Therefore, we have to postulate the existence of neurohumoral compensatory mechanisms in Wistar rats that allow the heart to maintain a normal systolic ejection. Peripheral adaptation has, for the moment, been poorly investigated, and hormonal alterations are not much known. Low plasma content in angiotensin I,33 elevated cortisol and atrial natriuretic peptide,34 35 and normal aldosterone35 have been reported in senescent rats, and very little is known about the neural regulation of vasomotion. When the aged heart is submitted to mechanical stress, it is still able to hypertrophy and develop further phenotypic changes in contractile proteins and SR Ca2+ ATPase.7 10 36 However, its latent myocardial dysfunction may result in a reduced capacity for response to pressure overload,3 31 calcium overload, or ischemia,37 38 leading to overt LV impairment.
SR Ca2+ ATPase Is the Single Calcium-Regulating Protein Modified in Renovascular Hypertension
In adult rats, we were able to obtain a moderate but sustained hypertension with mild LVH. In such a model of renovascular hypertension with increased Ang II, previous studies indicated alterations in the calcium handling system.39 In our study, SERCA2 is the unique calcium-regulating transcript to be modified, since both RyR2 and NCx mRNA levels were unchanged. A diminished SR Ca2+ ATPase mRNA concentration is known to be associated with corresponding changes in both protein density and activity24 and is correlated with a depressed relaxation velocity.7
Such a decrease of SR Ca2+ ATPase has already been observed in several models of mechanical overload, such as aortic stenosis,24 40 and in heart failure.41 42 However, in such models, a decrease of SERCA2 transcripts was observed only for more severe LVH, in all cases more than 50%. In our study, a decrease in SERCA2 transcripts is observed for a mild degree of LVH, suggesting the implication of mechanisms other than a single mechanical overload. On isolated cardiomyocytes, it has been reported that addition of Ang II induced the decrease of SERCA2 mRNAs, which suggests a direct role of this hormone on Ca2+ ATPase transcription.43 Such a direct role of Ang II in SR Ca2+ ATPase gene expression cannot be excluded in our model and could explain the decrease in SR Ca2+ ATPase mRNA levels observed, for the first time, for a mild degree of LVH.
The absence of changes in RyR2 and NCx mRNA concentrations observed during our renovascular hypertension indicated that these systems implicated in calcium handling were not yet impaired, at least at the molecular level. In all models of cardiac overload, alterations in RyR2 and NCx were reported only for severe hypertrophy. RyR2 mRNA levels are depressed only in LVH of about +100%17 or in heart failure.42 44 45 In contrast, and in similar conditions, NCx gene expression is activated, as for example after pulmonary artery stenosis in the cat, a model of severe acute pressure overload,16 and also in end-stage human heart failure.46 Our study suggests that as far as the calcium-regulating proteins are concerned, the change in genetic expression during LVH is a two-step procedure, with an initial modification of the SR Ca2+ ATPase, related to mechanical and/or hormonal factors, and then, in more severe forms, modifications of the ryanodine receptor and NCx.
Senescent Heart Is Under Mild Mechanical Overload
The same pattern was observed in the senescent left ventricle in terms of calcium-regulating proteins, ie, a decrease in SERCA2 and unchanged RyR2 and NCx mRNA contents, suggesting that the senescent heart is, in fact, a mechanically overloaded heart, at least in terms of calcium-regulating proteins.2 The senescent left ventricle is not anatomically hypertrophied, as previously reported7 9 ; nevertheless, mild myocyte hypertrophy is well documented.27 47 Our study indicates that SR Ca2+ ATPase is the only calcium-regulating protein involved in the calcium homeostasis impairment in the senescent myocardium, as in mild renovascular pressure overload. This diminution in mRNA content is associated with a diminution of the Ca2+ uptake by the SR.11 12 48 49 It can account for the increased duration of the calcium transient,2 6 the enhanced sensitivity to calcium in terms of automaticity,29 50 and the impaired active isotonic relaxation.7 Finally, our findings would also explain why, in clinical hypertensive cardiopathy, relaxation is depressed so early in the progression of the disease.
Senescent Heart Does Not Tolerate Renovascular Hypertension
The renovascular model of hypertension is associated with elevated plasma levels of Ang II. The clip diameter was similar in adult and aged rats and 25% higher than in previous studies21 to compensate for the increased diameter of the kidney artery in aged rats. Yet despite this precaution, all the senescent rats died within 2 weeks. Several studies using different models, such as aortic stenosis3 51 or the deoxycorticosterone acetate–salt model,7 have shown that the aged rats can tolerate a more increased level of blood pressure than that reported in our study. Thus, it is unlikely that the increased blood pressure was responsible for the mortality observed. However, in our renovascular model, the moderate level of blood pressure is accompanied by very high plasma levels of Ang II, as compared with the deoxycorticosterone acetate–salt model, which exhibits low renin-angiotensin system activity, or even abdominal aortic stenosis, which is associated with a modest and transitory increase in Ang II. In senescent rats, the circulating renin-angiotensin system is depressed33 although the cardiac renin-angiotensin system is activated.35 It could be suggested that the sensitivity to the deleterious effects of Ang II is enhanced in senescent hearts. The arrhythmogenic properties52 and coronary vasoconstrictive effects53 54 of Ang II could be exacerbated in the aged heart, which already presents spontaneous arrhythmias28 and alterations in coronary vascular tone.54 However, the exact physiological cause of this mortality remains to be elucidated.
In conclusion, the senescent left ventricle resembles a mildly overloaded heart in terms of changes in myocyte genetic expression but not in terms of collagen,18 with the same changes in isomyosin,7 adrenergic, and muscarinic receptors19 55 and also modifications of the calcium-regulating proteins involving only SR Ca2+ ATPase. The origin of this overload is likely to be an increased aortic impedance itself caused by dilatation of the large arteries and enhanced wall stiffness.2 Hemodynamic LV function is maintained despite underlying contractile dysfunction, indicating the existence of in vivo compensatory mechanisms. However, these alterations may explain the reduced capacity of adaptation to further stress such as myocardial ischemia.37 38
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Acknowledgments |
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This study was supported by grants from the Fédération Française de Cardiologie, Fondation pour la Recherche Médicale, and Société Française d'Hypertension Artérielle. The authors thank especially Drs Claude Sebban and Brigitte Decros for kindly providing the senescent rats, Dr Anne Marie Lompré for the kind gift of rat cardiac SERCA2 and RyR2 cDNAs, Dr Kenneth Boheler for the gift of rat cardiac NCx cDNA, Pascal Trouvé for technical assistance, and Carole Mennuni for meticulous care and handling of the rats.
Received May 30, 1996;
first decision July 5, 1996; first decision August 7, 1996;
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