Published online before print July 5, 2005, doi: 10.1161/01.HYP.0000173069.53699.d9
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(Hypertension. 2005;46:426.)
© 2005 American Heart Association, Inc.
Original Articles |
Angiotensin II–Mediated Phenotypic Cardiomyocyte Remodeling Leads to Age-Dependent Cardiac Dysfunction and Failure
From the Department of Physiology (A.A.D., L.M.D.D.), University of Melbourne, Australia; the Department of Medicine (Q.W., T.P.), University of Lausanne Medical School, Switzerland; the Department of Physiology (M.E.), University of Bern, Switzerland; and the Division of Biochemistry (S.M.R.), University of Tasmania, Australia.
Correspondence to Dr Lea M. Durham Delbridge, PhD, Department of Physiology, University of Melbourne, Parkville Victoria, 3010, Australia. E-mail lmd{at}unimelb.edu.au
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Abstract |
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Chronic elevation of plasma angiotensin II (Ang II) is detrimental to the heart. In addition to its hemodynamic effects, Ang II exerts cardiotrophic actions that contribute to cardiomyocyte remodeling. However, it remains to be clarified whether these direct actions of Ang II are sufficient to cause contractile dysfunction and heart failure in the absence of altered hemodynamic conditions. In this study, we used TG1306/1R (TG) mice that develop Ang II–mediated cardiac hypertrophy in absence of elevated blood pressure to investigate the phenotypic changes in cardiomyocytes during the adaptive response to chronic cardiac-specific endogenous Ang II stimulation. A 94-week longitudinal study demonstrated that TG mice develop dilated cardiomyopathy with aging and exhibit a significant increase in mortality compared with wild-type (WT) mice. Cardiac hypertrophy in TG mice is associated with cardiomyocyte hypertrophy (15 to 20 weeks: length +20%; 35 to 40 weeks: length +10%, width +15%) but not collagen deposition. In vivo analysis of cardiac function revealed age-dependent systolic and diastolic dysfunction in TG mice (
45% reduction in dP/dtmax and dP/dtmin at 50 to 60 weeks of age compared with WT). Analysis of isolated cardiomyocyte isotonic shortening showed impaired contractility in TG cardiomyocytes (30% to 40% decrease in rates of shortening and lengthening). In TG hearts, chronic Ang II exposure induced downregulation of the sarcoplasmic reticulum calcium pump (SERCA2) and diminution of Ca2+ transients, indicative of an underlying disturbance in calcium homeostasis. In conclusion, chronic Ang II myocardial stimulation without hemodynamic overload is sufficient to produce cardiomyocyte and cardiac dysfunction culminating in heart failure.
Key Words: aging • cardiac function • heart failure • hypertrophy • myocytes • renin-angiotensin system
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Introduction |
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The renin-angiotensin system (RAS) plays a crucial role in cardiovascular regulation via the activity of its effector, angiotensin II (Ang II), which is a potent vasoconstrictor and modulator of fluid balance. Ang II also exerts direct trophic actions on cardiac cells, inducing cardiomyocyte hypertrophy and fibroblast proliferation.1
Local Ang II production is of key importance in the pathophysiology of the RAS in the heart.2 Gradual increases in cardiac Ang II levels have been reported in experimental models and clinically during the development of heart failure.3,4 Numerous studies have demonstrated the efficacy of RAS blockade in the treatment of cardiac remodeling and heart failure, independently of the reduction in systemic blood pressure.5,6 Elevated cardiac angiotensinogen levels are observed in various animal models of pressure and volume overload cardiac hypertrophy, in which Ang II is considered to contribute significantly to cardiac remodeling through its growth-promoting properties.7,8
In addition, Ang II is an important modulator of cardiac and cardiomyocyte contractility. Acute in vitro and in vivo exposure of the myocardium to Ang II usually (but not always) increases contractility.9–12 In contrast, Ang II has been shown to exacerbate contractile dysfunction in experimental models of pressure-overload cardiac hypertrophy13 and pacing- or infarction-induced heart failure.14,15
Little is known about the chronic effects of high levels of intracardiac Ang II on cardiac function. In particular, the hemodynamics-independent impact of chronic Ang II overproduction in the heart on cardiomyocyte contractility has yet to be evaluated. The present study investigates the TG1306/1R (TG) mouse model, which exhibits cardiac-specific elevation of Ang II production.16,17 In the TG, which has been shown previously to develop Ang II–mediated cardiac hypertrophy in the absence of elevated blood pressure, we evaluate the direct effects of endogenous cardiac Ang II overproduction on cardiomyocyte and heart morphology and function.
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Methods |
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Methods are detailed in the online supplement, available at http://www.hypertensionaha.org.
Experimental Model
We reported previously the generation of a transgenic heterozygous mouse, the normotensive and hypertrophic TG, which carries multiple copies of the rat angiotensinogen gene under control of the 
-myosin heavy chain promoter, and exhibits significantly elevated angiotensinogen expression from early development through to senescence.16–18 Experiments were conducted on male mice 15 to 20, 25 to 30, 35 to 40, and 50 to 60 weeks of age. Longevity data were also collected for mice over a period of 94 weeks.
Cardiac Function, Heart Histology, and Cardiomyocyte Morphometry
Whole heart contractility in conscious mice was determined by the measurement of left ventricular (LV) pressure derivative dP/dt as described previously using a polyether block amide (Pebax) catheter.19 For histological analysis, transverse sections were stained (Van Gieson’s) and analyzed for collagen content by computer-assisted densitometric morphometry (collagen expressed as percentage of total sectional area).
Cardiomyocyte Contractility and Cai Measurements
Isolated ventricular cardiomyocytes were prepared by collagenase retrograde aortic perfusion methods described previously.10 Cell dimensions were measured under bright-field microscopy (100 cardiomyocytes per heart). Cardiomyocyte contractility was evaluated using a rapid imaging system, as described previously.10 Cells were paced using a frequency ramp (1.5, 3.0, 4.0, and 5.0 Hz). For each contraction cycle, a range of normalized contractile parameters was automatically computed and averaged (see Table 3 legend).
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Caffeine-induced Ca2+ transients were evaluated in cardiomyocytes isolated from 25- to 30-week-old mice by fluo-3 fluorescence measurements using confocal laser-scanning microscopy as described previously.20 Using stimulation conditions to ensure comparable sarcoplasmic reticulum (SR) Ca2+ loading conditions, Cai transient kinetics after application of caffeine were evaluated.
Western Blot Analysis of the SR Ca2+ ATPase
SR Ca2+ ATPase (SERCA2) levels were determined by Western blot from ventricular homogenate protein extract using goat anti-mouse polyclonal antibodies and peroxidase-conjugated secondary anti-goat IgG antibodies. Bands were identified using chemiluminescence.
Statistics
Results are expressed as mean±SEM. One-way and 2-way ANOVAs were applied as indicated to test for differences (P<0.05) between age-matched TG and wild-type (WT) mice.
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Results |
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Survival and the Hypertrophic Phenotype
Compared with WT littermate controls, TG mice exhibited a significant increase in mortality (Figure 1) over the 94-week longitudinal study (WT 83% survival versus TG 46% survival). Postmortem analysis showed that premature mortality in the TG group was predominantly associated with occurrence of a dilated cardiac phenotype, whereas the survivor TG mice exhibited a concentric hypertrophic phenotype (Figure 2A through 2C). To understand whether remodeling severity and lethality were associated with variable cardiac Ang II production levels, we generated a small number of homozygous TG mice harboring double the transgene complement. These mice exhibited a dilated cardiomyopathy and died prematurely after 7 to 10 days (Figure 2D through 2F).
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To further evaluate the effects of Ang II on cardiac structure before the overt appearance of the dilated phenotype, we investigated the cardiac morphology of 15- to 20-week-old and 35- to 40-week-old TG mice compared with age-matched WT littermates (Table 1). In these TG mice, a concentric growth pattern was consistently observed, with significant increase in LV wall thickness at both ages in the absence of significant chamber dilation. Thus, the dilated phenotype observed in about half the aged TG mice appears to represent a transition process that occurs later in life, in association with increased mortality.
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Densitometric analysis of histological sections showed that, despite a significant increase in cardiac mass at both ages, there was no evidence of an increase in interstitial fibrosis (Table 1). Additionally, qualitative examination of histological sections in 45- to 94-week-old WT and TG mice did not identify any age- or genotype-dependent variations in interstitial collagen staining. These observations were also confirmed in 1-week-old WT versus heterozygote and homozygote TG (Figure 2). Therefore, the increased cardiac mass appeared to result primarily from cardiomyocyte remodeling rather than collagen deposition. Indeed, the dimensions of adult LV cardiomyocytes were found to be greater in TG hearts. Mean cell length was increased significantly in the cardiomyocyte population of TG mice at both ages. Interestingly, in the older TG myocytes only, a significant increase in cell width was also observed (Table 1).
Depressed Cardiac Function In Vivo Associated With Cardiomyocyte Remodeling
To determine whether hypertrophic remodeling was associated with cardiac dysfunction in vivo, we assessed LV contractility of 15- to 20-week-old and 50- to 60-week-old TG mice by intraventricular catheterization (Table 2). In the younger TG mice, early evidence of relaxation abnormality was detected as a significant increase in the time constant of isovolumic pressure decline (tau). With increased maturity, more extensive signs of systolic and diastolic dysfunction were observed, with an 45% decrease in rate of LV pressure development (+dP/dtmax) and relaxation (–dP/dtmin) accompanying the further deterioration in relaxation time constant in TG mice. Our results confirmed that even at 50 to 60 weeks of age, TG mice remained normotensive despite the development of Ang II–dependent cardiac hypertrophy.16,17
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Cardiomyocyte Contractile Dysfunction in Transgenic Mice
Cardiomyocyte excitation–contraction coupling was assessed in vitro by measurement of isotonic shortening of single cardiomyocytes over a range of pacing frequencies (1.5 to 5.0 Hz). Cells of similar dimension were selected for this comparison (length 129.0±13.0 µm length and width 29.0±3.0 µm) to avoid confounding the data with size-dependent performance factors.
Comparisons between age-matched TG and WT at 5 Hz showed that both rates of shortening and lengthening (maximal rate of cell shortening [MRS] and maximal rate of cell lengthening [MRL]) were reduced in the TG myocytes relative to WT controls (Table 3). The slowest contraction kinetics were observed in the group of older TG myocytes. Genotype-dependent prolongation effects on contraction cycle timing were also evident at both ages: the latency (To), the shortening and lengthening periods, and total cycle times were significantly longer in TG than WT myocytes. These genotype differences were maintained across the range of pacing frequencies (Figure 3). A negative frequency "staircase" was observed for all parameters at both ages, except for the latency (To), which increased with frequency (Figure 3D).
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P<0.05, pacing frequency effect.Across the range of pacing frequencies, WT and TG myocytes from older animals exhibited reduced maximal shortening (%S) and rate of shortening (MRS), together with an abbreviated duration of shortening time (Tm–To) relative to their younger counterparts (Figure 3A, 3B, and 3F). These findings demonstrate that in mouse myocytes, ageing, per se, regardless of genetic type, is associated with blunted and abbreviated shortening activity. Interestingly, neither the rate of lengthening (MRL) nor cycle time (Tf–To) exhibited age-dependent modulation in the TG (Figure 3C and 3E).
SERCA2 Expression and Cardiomyocyte Ca2+ Transients
Because contraction kinetics are largely dependent on SR Ca2+ homeostasis, we investigated the expression of the SR SERCA2 Ca2+ pump in the hearts of 15- to 20-week-old TG and WT mice (Figure 4A and 4B). Western blot analysis showed an 80% downregulation of the SERCA2, suggesting that alterations in Ca2+ handling are potentially involved in relaxation dysfunction in TG hearts. This is supported by measurements of Ca2+ transients in cardiomyocytes of 25- to 30-week-old mice. The amplitude of Ca2+ transient in TG myocytes was 50% decreased when compared with WT cells (Figure 4C and 4D). In addition, the decay of the caffeine-induced Ca2+ transients was prolonged in TG myocytes compared with WT (WT 
=798±177 ms; TG =1508±412 ms; P<0.05).
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Discussion |
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The present study demonstrates that chronic overexpression of cardiac Ang II is sufficient to induce the development of 2 contrasting hypertrophic phenotypes in aged transgenic mice. Those TG animals that died during the 94-week observation period exhibited a dilated hypertrophic phenotype, whereas their longer-surviving TG littermates were characterized by a concentric hypertrophy. These findings indicate that the concentric hypertrophic state is associated with a degree of functional compensation and survival, and that the dilated phenotype emerges in association with increased mortality. Our results also suggest that functional decompensation precedes overt myocardial dilation and support the hypothesis that concentric and dilated hypertrophy share some common cellular pathways of development.21
Our observations in the homozygous TG mice suggest that an increased expression of the angiotensinogen transgene, and therefore of Ang II production, exacerbates the severity of the cardiac phenotype observed, indicating that the type and severity of Ang II–mediated myocardial remodeling are time- and angiotensinogen gene copy–dependent. Our previous studies on TG mice already demonstrated that the trophic actions of Ang II on the heart are mediated by Ang II type 1 (AT1) receptors.16,17 We have also shown that the ratio of expression of receptor subtypes (AT1/AT2) in heterozygous TG is not different than for WT.22
Our study extends previous observations that chronic overexpression of cardiac Ang II in transgenic mice is sufficient to induce blood pressure–independent cardiac hypertrophy without signs of fibrosis.23 Although qualitative changes in collagen content cannot be excluded, our morphological analysis suggests that cardiac remodeling results almost entirely from cardiomyocyte hypertrophy rather than extracellular matrix deposition. As observed previously,24,25 collagen concentrations in the LV free wall were substantially lower than that in the right ventricle, but no age- or genotype-specific differences were detected. Of interest is the apparent similarity between the cardiac phenotype described here and that observed in transgenic mice overexpressing the Gq protein specifically in the heart. The latter animals are characterized by cardiac decompensation in the absence of cardiac fibrosis and pressure overload.26,27 Because signaling pathways mediated by AT1 receptors are known to be Gq linked,28 the cardiac remodeling in the TG mice may be an outcome of specific activation of cardiomyocyte AT1 Gq-coupled receptors.
The present study demonstrates that long-term overexpression of cardiac Ang II has a detrimental effect on excitation–contraction coupling in the myocardium, even when there is no elevation of afterload. Myocardial remodeling in 50- to 60-week-old transgenics is associated with decreased in vivo contractility and relaxation, which is preceded by a more subtle sign of relaxation delay observed in hearts of 15- to 20-week-old TG mice. These findings indicate that chronic overproduction of Ang II in the heart causes systolic dysfunction and early onset of diastolic dysfunction (prominent signs of heart failure). Myocyte contractility experiments complement the in vivo data and show that impaired relaxation (MRL) and prolonged contractile cycle time (Tf–To) in younger TG cardiomyocytes precede later emergence of shortening dysfunction (MRS) and increased latency (To). This would suggest that the hypodynamic performance of TG hearts in vivo reflects fundamental abnormalities in cardiomyocyte excitation–contraction coupling.
Additionally, these data emphasize the important role played by aging in the development of contractile dysfunction. Cardiomyocytes from older TG and WT exhibit reduced shortening and an abbreviated shortening time. In the WT, aging is associated with a reduction in the rate of myocyte lengthening during relaxation, but in the TG, in which this parameter is already dramatically suppressed at 15 to 20 weeks, no further age-dependent decrement is observed. Thus, aging is associated with deterioration of cardiomyocyte kinetics consistent with the development of failure. Increased levels of Ang II in the heart accelerates the onset of relaxation impairment and exacerbates shortening dysfunction and latency.
Alterations in cardiomyocyte and myocardial function in these mice are associated with the marked reduction in the expression of the SR SERCA2 protein, diminished systolic Ca2+ levels, and prolongation of Ca2+ transients (Figure 4). Downregulation of the SERCA2 Ca2+ pump would suppress the reuptake of Ca2+ into the SR delaying myocyte relaxation, reduce the levels of releasable SR Ca2+, and erode systolic function. In general, differences in TG and WT cardiomyocyte contractile parameters were proportionally consistent over the range of pacing frequencies evaluated, indicating that SR loading rather than interval-dependent excitation–contraction coupling recovery, is altered in the TG.29,30 These results accord with findings in the Gq-overexpressing transgenic, in which cardiomyocyte dysfunction (decreased rates of shortening and lengthening) is associated with downregulation of SERCA2 and prolonged duration of Ca2+ transients.31 The specific means by which chronic elevation of cardiac Ang II perturbs cardiomyocyte Ca homeostasis remains to be elucidated. Further molecular and electrophysiological investigations are necessary to explore how cellular compensatory mechanisms are recruited to sustain excitation–contraction coupling in the TG myocytes before the eventual decompensation transition associated with dilated hypertrophy and ultimately failure.
Perspectives
Our study indicates that chronic activation of the RAS in the heart in absence of hemodynamic overload produces cardiomyocyte and cardiac dysfunction. In particular, endogenous overproduction of cardiac Ang II is sufficient to induce the development of an evolving cardiac phenotype ultimately resulting in dilation and heart failure. These phenotypic alterations likely result from a change in gene expression in cardiomyocytes induced by Ang II. In this regard, the TG model provides a valuable experimental tool for elucidating the cellular pathways responsible for the transition from compensated concentric hypertrophy to dilation and cardiac failure.
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Acknowledgments |
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This work was partially funded by Swiss National Science Foundation grants 32-OOBO-102154/1 (T.P.) and 31-68056.02 (M.E.) and the Swiss Cardiovascular Research and Training Network (A.A.D., Q.W.). We acknowledge doctoral scholarship support (A.A.D.) from the Roche Research Foundation (Fli7stm 98-120), the Swiss National Science Foundation, and the University of Melbourne. We thank Dr Gregory Jones for valuable intellectual contribution and Jim Pringle for excellent technical assistance.
Received February 8, 2005; first decision February 26, 2005; accepted May 27, 2005.
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