Decompensation of Pressure-Overload Hypertrophy in Gαq-Overexpressing Mice
Background—Receptor-mediated activation of myocardial Gq signaling is postulated as a biochemical mechanism transducing pressure-overload hypertrophy. The specific effects of Gq activation on the functional and morphological adaptations to pressure overload are not known.
Methods and Results—To determine the effects of intrinsic myocyte Gαq signaling on the left ventricular hypertrophic response to experimental pressure overload, transgenic mice overexpressing Gαq specifically in the heart (Gαq-25) and nontransgenic siblings underwent microsurgical creation of transverse aortic coarctation and the morphometric, functional, and molecular characteristics of these pressure-overloaded hearts were compared at increasing times after surgery. Before aortic banding, isolated Gαq-25 ventricular myocytes exhibited contractile depression (depressed +dl/dt and −dl/dt) and Gαq-25 hearts showed a pattern of fetal gene expression similar to the known characteristics of nontransgenic pressure-overloaded mice. Three weeks after transverse aortic banding, Gαq-25 left ventricles hypertrophied to a similar extent (≈30% increase) as nontransgenic mice. However, whereas nontransgenic mice exhibited concentric left ventricular remodeling with maintained ejection performance (compensated hypertrophy), Gαq-25 left ventricles developed eccentric hypertrophy and ejection performance deteriorated, ultimately resulting in left heart failure (decompensated hypertrophy). The signature hypertrophy-associated progress of fetal cardiac gene expression observed at baseline in Gαq-25 developed after aortic banding of nontransgenic mice but did not significantly change in aortic-banded Gαq-25 mice.
Conclusions—Intrinsic cardiac myocyte Gαq activation stimulates fetal gene expression and depresses cardiac myocyte contractility. Superimposition of the hemodynamic stress of pressure overload on Gαq overexpression stimulates a maladaptive form of eccentric hypertrophy that leads to rapid functional decompensation. Therefore Gαq-stimulated cardiac hypertrophy is functionally deleterious and compromises the ability of the heart to adapt to increased mechanical load. This finding supports a reevaluation of accepted concepts regarding the mechanisms for compensation and decompensation in pressure-overload hypertrophy.
Myocardial hypertrophy is typically the adaptive response of the heart to increased hemodynamic load and initially preserves chamber function by normalizing chamber wall stress.1 In the short term, pressure-overload hypertrophy results in thickening of ventricular walls (and of cardiac myocytes) and increased sarcomeric protein content with expression of fetal cardiac genes and gene products.1 2 However, if the mechanical load on the heart is not relieved, the pressure-overload hypertrophied ventricle dilates, contractile function diminishes, and the heart ultimately fails.1 3 4 While it is clear that mechanical stress is the stimulus for cardiac hypertrophy, the biochemical signals and transducers of this response have not been clearly elucidated. Studies in cultured neonatal cardiac myocytes have clearly shown that stimulation of Gq-coupled receptors causes myocyte hypertrophy with increased cell size and protein content and increased expression of hypertrophy-associated genes.5 6 7 8 9 10 Because experimental pressure-overload hypertrophy in rodents and clinical pressure overload in humans is also characterized by myocyte enlargement and reexpression of fetal cardiac genes,11 12 13 14 15 it has been postulated that receptor-mediated autocrine or paracrine stimulation of Gq signaling is a biochemical mechanism transducing pressure-overload hypertrophy of the heart.16
Cardiac-specific transgenesis has made it possible to test the hypothesis that activation of myocardial Gq signaling (independent of extracardiac effects) can directly stimulate cardiac hypertrophy. The first transgenic murine cardiac hypertrophy model to support a Gq-mediated mechanism of hypertrophy signaling was overexpression of the constitutively activated Gq-coupled α1B adrenergic receptor (CAα1BAR).17 Chronic activation of phospholipase C in the hearts of these animals resulted in hypertrophy defined as cardiomegaly, increased cardiac myocyte cross-sectional area and increased atrial natriuretic factor (ANF) expression. Thus these animals develop a form of cardiac hypertrophy that resembles murine pressure-overload hypertrophy.11 More recently, cardiac-specific overexpression of the α-subunit of the Gq GTP-binding protein generated mice that developed a somewhat different form of cardiac hypertrophy, with increased whole heart weight, increased cardiomyocyte cross-sectional area, and recapitulated expression of fetal cardiac genes.18 These mice had normal ventricular weights and wall thickness but depressed left ventricular contractility as assessed by echocardiographic and invasive hemodynamic techniques.
Because receptor-mediated activation of Gαq/phospholipase C signaling in the heart is postulated as an autocrine/paracrine pathway mediating pressure-overload hypertrophy,16 19 and because Gαq overexpressors exhibit myocyte hypertrophy and hypertrophy-associated gene expression without ventricular remodeling,18 the current studies were undertaken to test the notion that basal intrinsic activation of cardiac myocyte Gαq signaling in Gαq overexpressors would enhance the cardiac hypertrophic response to extrinsic mechanical loading. A microsurgical model of transverse aortic constriction was used so that the morphological, functional, and molecular adaptations to pressure overload could be compared in Gαq transgenic and nontransgenic mice.
Construction of cardiac-specific Gαq-overexpressing transgenic mice has been described elsewhere.18 Briefly, expression of the 1.46 kb murine Gαq cDNA was driven by the full length murine α myosin heavy chain (MHC) promoter. Three independent germ lines were established with incorporation of ≈9, 25, and 40 transgene copies. The current study used the Gαq-9 and Gαq-25 lines (9 and 25 transgene copies, respectively), the baseline characteristics of which have previously been reported.18 Because Gαq-25 mice exhibit atrial enlargement, which is probably a consequence of high level embryonic αMHC-driven transgene expression and developmental abnormalities, all analyses were performed on ventricles or ventricular tissue only.
Microsurgical techniques were used to band the transverse aortae of 12-week-old male Gαq transgenic mice and nontransgenic littermates, creating pressure overload, as previously described by ourselves and others.11 12 Briefly, anesthetized and ventilated 12-week-old mice had the left thorax opened at the second intercostal space and a 7–0 nylon suture ligature was tied around the transverse aorta against a 26-gauge needle. We have previously shown that this technique results in a 45 to 50 mm Hg gradient between the ascending and descending aorta as simultaneously measured in right and left carotid arteries.12 In the current studies overall intraoperative mortality was ≈15%, and 7-day operative mortality was ≈8% in both transgenic and nontransgenic mice. Aortic-banded mice were maintained for 48 hours, 1 week, or 3 weeks and were compared with nonbanded transgenic or nontransgenic mice as indicated.
Assessment of Cardiac Hypertrophy and Function
Cardiac function of aortic-banded mice was evaluated noninvasively with echocardiography at defined intervals 1 day before and 1, 2, and 3 weeks after surgery, using previously described methods.18 20 Left ventricular percent fractional shortening (LVFS), mass (LVM), and end-diastolic wall thickness/radius (h/r) were calculated as previously reported.20 The quantitative measurements represent consensus estimates by two different investigators (Y.S. and B.D.H.), and interobserver variability was < 10%.
At times corresponding in part with the echocardiographic studies (before banding, 48 hours, 1 week, and 3 weeks after banding), cohorts of aortic-banded mice were euthanatized for morphometric analysis of cardiac chamber size and for measurements of cardiac gene expression, using previously described methods.18
Because some aortic-banded Gαq transgenic mice developed overt heart failure and individual mice exhibited varying degrees of wasting after surgery, organ weights were indexed to tibial length rather than body weight. Tibial lengths were determined post mortem: Both lower limbs were amputated at mid-femur, dissected free of skin, labeled, and placed in active cultures of Dermisted beetles (South Carolina Biotechnology) overnight. The cleaned tibias were disarticulated and their lengths measured with digital calipers. The average length of both tibias was used to index organ weights.
Myocyte cross-sectional area was measured with fluorescein-tagged wheat germ agglutinin staining of frozen histological sections, as previously described.18
Assessment of Mechanical Function in Isolated Cardiac Myocytes
The contractile function of isolated unloaded ventricular cardiac myocytes paced at 0.25 Hz was assessed as previously described.12 Four to six myocytes per animal were studied, the results pooled and considered as a single n. Herein are reported results from six pairs of (Gαq-25 and nontransgenic) mice.
Assessment of cardiac gene expression was by RNA dot blot analysis as previously described.18 Briefly, total RNA was extracted from ventricular tissue and applied (2 μg/dot) to nylon membranes. Strips of membranes were hybridized with 32P-labeled antisense oligonucleotides specific for the indicated genes and quantitated with the use of a phosphoimager. Because GAPDH was not regulated in either Gαq transgenic or aortic-banded mice, cardiac gene expression was normalized to GAPDH for quantitative analysis.
Data are reported as mean±SEM. Multiple group comparison was by one-way ANOVA followed by the Bonferroni procedure for comparison of means. Two-tailed Student’s t test was used to compare transgenic with nontransgenic specimens under identical conditions. Significance was defined as P<.05.
As previously reported, the baseline characteristics of cardiac specific Gαq-overexpressing mice differ in relation to transgene copy number and level of Gαq protein expressed.18 The lowest expressing Gαq-9 line, with Gαq protein levels twice that of nontransgenic mice, was phenotypically normal, with no evidence of cardiac enlargement, no fetal cardiac gene expression, and normal cardiac function. To examine the possibility that a cardiac phenotype could be provoked by pressure overload in these mice, Gαq-9 mice and nontransgenic siblings underwent aortic banding and were followed for 48 hours, 1 week, and 3 weeks. The extent and character of left ventricular hypertrophy and the pattern of fetal gene expression was identical in Gαq-9 mice compared with nontransgenic controls (not shown). Therefore these findings are not presented in detail.
A higher expressing Gαq-25-overexpressing mouse line (fourfold increase over nontransgenic myocardial Gαq protein levels) exhibited baseline myocyte hypertrophy and increased hypertrophy-associated gene expression with impaired in vivo left ventricular ejection performance.18 To determine whether the observed in vivo functional impairment was a consequence of myocyte contractile depression or of altered ventricular geometry, the mechanical properties of ventricular myocytes from Gαq-25 mice and nontransgenic sibling controls were assessed. These results were then compared with our prior results on isolated myocytes from transverse aortic-banded male FVB/N nontransgenic mice12 (Fig 1⇓). Extent of unloaded shortening was not altered by either Gαq overexpression or aortic banding. However, the peak rates of myocyte shortening and relengthening were depressed to similar extents in Gαq-25 and nontransgenic aortic-banded ventricular myocytes compared with their respective controls. Although the myocyte studies comparing Gαq-25 with nontransgenic aortic-banded mice involve historical data, the nontransgenic, nonbanded FVB-N controls in both data sets are essentially indistinguishable. Thus the observed in vivo depression of left ventricular contractility and ejection performance in Gαq-25 mice appears to be a consequence of impaired cardiac myocyte contractility and, as with the previously noted increased myocyte cross-sectional area and fetal gene expression,18 is a characteristic shared by Gαq transgenic and pressure-overload hypertrophied mice.11 12
To further explore the relationship of intrinsic Gαq signaling and external mechanical load on cardiac hypertrophy, pairs of Gαq-25 mice and nontransgenic littermates underwent transverse aortic banding. The results from morphometric analysis of nontransgenic and Gαq transgenic mice before and at various times after transverse aortic banding are shown in Table 1⇓. Before aortic banding, 12-week-old Gαq transgenic mice had significantly greater atrial and whole heart weights but not left or right ventricular weights compared with nontransgenic animals. A slight but statistically significant increase in lung weight was observed in Gαq overexpressors, suggesting the presence of mild pulmonary congestion in some of these animals. In contrast, liver weights were not increased.
Three pairs of animals were studied 48 hours after aortic banding (Table 1⇑). At this early time point there was no significant change from baseline in cardiac chamber weights, body weight, or the degree of pulmonary congestion. Thus measurable morphometric hypertrophy had not yet occurred 2 days after acute induction of pressure overload.
1 week after aortic banding there was an increase in left ventricular weight, which, when corrected for tibial length, was significantly greater than prebanding values in both nontransgenic and Gαq transgenic mice. In contrast, there were no significant changes in the weights of the other cardiac chambers, of lungs, or of liver when compared with prebanding values. Thus by morphometric criteria, 1 week after transverse aortic banding both Gαq transgenic and nontransgenic mice exhibited a “compensated” form of pressure overload left ventricular hypertrophy.
When followed for 3 weeks, clear differences between the transgenic and control mouse responses to aortic banding became apparent. The weights of left ventricles from nontransgenic mice (indexed to tibial length) had increased by ≈30% compared with prebanding. This compares with a nearly identical 26% increase in left ventricular weight of the Gαq overexpressors. Right ventricular weights did not change, indicating a strictly ipsilateral hypertrophic response to left ventricular pressure overload in all animals. Most striking however, was the development of pulmonary congestion in the Gαq transgenic mice. Lung weights corrected for tibial length increased by 56% in Gαq overexpressors but were not significantly increased in the banded nontransgenic mice. Taken together, these morphometric studies demonstrated an equivalent degree of left ventricular hypertrophy in pressure-overloaded Gαq transgenic and nontransgenic mice. However, control mice were functionally compensated as demonstrated by the absence of pulmonary congestion, whereas Gαq overexpressors “decompensated” and, at 3 weeks after banding, had developed overt left heart congestive failure.
The morphometric evidence suggesting functional cardiac deterioration in pressure-overloaded Gαq transgenic mice was confirmed by serial echocardiographic studies of mice before and after aortic banding. Echocardiographic measures of left ventricular systolic and diastolic dimensions and septal and posterior wall thicknesses are shown in Table 2⇓, and the derived left ventricular mass, fractional shortening, and ratio of wall thickness to ventricular dimension (h/r) are illustrated in Fig 2⇓. Consistent with the morphometric results, the increase in left ventricular mass in pressure-overloaded Gαq overexpressors was comparable to that of control mice at various times after aortic banding (Fig 2A⇓). Interestingly however, the resulting alterations in left ventricular function and geometry were strikingly different. Fig 2B⇓ shows that left ventricular fractional shortening of nontransgenic mice was maintained at normal preband levels during pressure-overload hypertrophy. This contrasts with the progressive deterioration of left ventricular shortening observed in Gαq transgenic mice. A likely explanation for this difference in left ventricular ejection performance is the difference in ventricular modeling. Control mice developed the expected concentric pressure-overload hypertrophy as defined by an increase in left ventricular wall thickness compared with chamber dimension (Fig 2C⇓). In contrast, Gαq transgenic mice developed eccentric hypertrophy in that they maintained only the “normal” ratio of wall thickness to ventricular dimension.
Pressure-overload hypertrophy is typically accompanied by an increase in cardiac myocyte width, and Gαq overexpressors exhibit increased myocyte cross-sectional area at baseline.18 As a third measure of hypertrophy, myocyte cross-sectional area was determined in nonbanded, 48-hour, 1-week and 3-week banded nontransgenic and Gαq-overexpressing mice. The results, shown in Fig 3⇓, confirm the baseline hypertrophy of Gαq myocytes and demonstrate an increase in both Gαq and nontransgenic cardiomyocyte area at 1 week after banding. Interestingly, control banded myocytes continued to hypertrophy at 3 weeks, whereas Gαq myocytes showed no further increase after 1 week after banding.
We considered that the abnormal cardiac functional and geometric responses to pressure overload in Gαq transgenic mice could be related to differences in hypertrophy-associated gene expression. We and others have previously demonstrated increased expression of ANF and the β-isoform of myosin heavy chain (βMHC) in pressure-overloaded mice11 12 and at baseline in Gαq transgenic mice18 (Fig 4⇓). Therefore we compared the mRNA levels of these and other cardiac genes, each measured as a function of time after transverse aortic banding. Nonbanded Gαq overexpressors expressed significantly higher levels of ANF, βMHC, and α-skeletal actin than nonbanded nontransgenic mice, consistent with the known characteristics of this transgenic mouse.18 Aortic banding of nontransgenic mice resulted in increased expression of these same genes. Nevertheless, equivalence in expression levels of ANF and βMHC mRNA was never achieved in banded nontransgenic mice compared with either nonbanded or banded Gαq mice. Interestingly, regulation of hypertrophy-associated gene expression was minimal in pressure-overloaded Gαq overexpressors. Thus we found no evidence that distinct molecular programs of hypertrophy exists for “compensated” and “decompensated” hypertrophy.
The current study compares the morphological, functional, and molecular changes in the left ventricles of wild-type and Gαq-overexpressing mice subjected to surgical creation of a transverse aortic coarctation. Based on the notion that autocrine or paracrine stimulation of myocardial Gq-coupled receptors transduces pressure-overload hypertrophy,16 19 we expected to find an enhanced hypertrophic response in aortic-banded Gαq overexpressors. We found that aortic-banded nontransgenic FVB/N mice rapidly developed concentric left ventricular hypertrophy, which maintained normal left ventricular ejection performance in the face of increased hemodynamic load. However, cardiac overexpression of Gαq and the resulting intrinsic activation of hypertrophy signaling so modified the physiological response to the mechanical stress of aortic banding that rather than compensatory concentric hypertrophy, a maladaptive form of eccentric hypertrophy developed, which, after 3 weeks, progressed to overt congestive heart failure.
A fascinating aspect of the cardiac decompensation observed in pressure-overloaded Gαq overexpressors is the inverse correlation between ventricular function and extent of hypertrophy, measured at different times after aortic banding. It was possible that the basal contractile depression in Gαq overexpressors would so impair left ventricular performance that the acute hemodynamic stress of transverse aortic banding would simply not be tolerated. This was not the case, however, as 1 week after aortic banding Gαq mice were fully compensated with no significant decline in left ventricular shortening or increase in lung weight, and with appropriate increases in left ventricular mass and cardiomyocyte cross-sectional area. Over the following 2 weeks however, left ventricular performance deteriorated and pulmonary congestion developed. This suggests that in mice in which Gαq overexpression activates intrinsic hypertrophic signaling pathways; the more extensive the hypertrophy, the more severe the functional consequences. This notion is supported by our previous observation that mice with the highest levels of Gαq expression (achieved by interbreeding two separate transgenic lines) developed the greatest extent of hypertrophy and degree of functional impairment.18
It was unexpected that pressure-overload hypertrophy in mouse overexpressing Gαq at fourfold wild-type levels would have the dramatic functional effects observed in Gαq-25 mice but would have no measurable effect on hypertrophy development or left ventricular function in aortic-banded mice overexpressing Gαq at twice control levels (Gαq-9). As previously reported,18 at baseline the Gαq-9 transgenic line exhibits no hypertrophy, hypertrophy-associated gene expression, or functional phenotype. It was possible that if pressure-overload hypertrophy is transduced in part through receptor-mediated activation of Gq signaling, a minimal increase in Gαq level would either augment or accelerate the hypertrophic response. Our negative results suggest that overexpression of a nonactivated Gαq protein requires a threshold level of expression to stimulate hypertrophy signaling and that this is not achieved at twice nontransgenic levels.
Negative results from Gαq-9 mice notwithstanding, the idea that humoral factors that activate Gαq signaling pathways in the heart are a physiological stimulus for myocardial hypertrophy is directly supported by numerous examples of such agents causing hypertrophied growth of cultured neonatal rat cardiomyocytes as well as by our findings in the Gαq-25 and Gαq-40 overexpressors and other transgenic mouse models. Angiotensin II,5 6 phenylephrine,7 8 endothelin,9 and prostaglandin F2α10 each stimulate neonatal cardiomyocyte hypertrophy through activation of Gαq-coupled cardiomyocyte receptors. Evidence that similar pathways can transduce pressure-overload cardiac hypertrophy in the intact organism is provided by the antihypertrophic effects of angiotensin-converting enzyme inhibitors or angiotensin receptor antagonists, independent of their antihypertensive actions.21 22 Thus it was perhaps not surprising that Gαq-overexpressing mice develop a form of cardiac hypertrophy that is independent of hemodynamic load.18 What was unexpected however, was the associated left ventricular contractile dysfunction.
An important facet of these studies is the demonstration of a contractile defect in isolated ventricular Gαq cardiac myocytes. Gαq overexpressors have significantly slower heart rates, atrial enlargement, and mildly dilated ventricles compared with nontransgenic mice.18 It was possible that these or other factors could adversely affect global ventricular function in the manner we have observed using invasive hemodynamic or echocardiographic measures. However, impaired contractile function of Gαq-overexpressing ventricular myocytes, which is independent of heart rate and cardiac chamber geometry, strongly supports the notion that intrinsic characteristics of Gαq-stimulated hypertrophy play a major role in depressing ventricular contractility.
Conventional wisdom regarding the development, maintenance, and eventual failure of pressure-overload hypertrophy holds that the short-term adaption conferred by hypertrophy normalizes wall stress and maintains ventricular function but that unrelieved hemodynamic stress eventually overwhelms these adaptive processes and results in decompensated cardiac failure.1 3 4 However, basal left ventricular and isolated cardiac myocyte contractile dysfunction in Gαq overexpressors (current study) and pressure-overloaded nontransgenic mice12 suggest that this form of cardiac hypertrophy can be intrinsically dysfunctional and supports a reevaluation of the concepts of “compensated” and “decompensated” pressure-overload hypertrophy. In this regard, the notion that hemodynamic stress results in a dysfunctional “cardiomyopathy of pressure overload” rather than compensated hypertrophy,23 24 if mediated by Gαq signaling, could explain the current findings. This view is held by Katz,24 who notes that increased muscle mass and favorable changes in left ventricular geometry in pressure-overload hypertrophy occur at the expense of fundamental alterations in sarcomeric protein content due to the reexpression of fetal protein isoforms. Thus an inevitable consequence of the short-term functional benefit provided by increased wall thickness is an unfavorable alteration of myocardial protein content, which then predisposes the overloaded heart to functional decompensation over the long term.
In the present studies, nontransgenic mice responded to pressure overload with the expected concentric hypertrophy, fetal gene expression, and maintenance of normal ejection performance, that is, “compensated” hypertrophy. In contrast, Gαq overexpressors decompensated after aortic banding despite an increase in left ventricular mass equivalent to nontransgenic mice. The hypertrophy gene expression program was active in Gαq overexpressors before application of the mechanical stress of aortic banding, and we have found that unstressed Gαq-25 transgenic mice have a normal lifespan without development of heart failure (G.W. Dorn, unpublished results, 1997). Thus Gαq overexpressors represent an intermediate phase of hypertrophy, neither fully compensated nor decompensated, which we have designated “compromised.”
It is instructive to compare the Gαq overexpressor phenotype with two other transgenic mouse models of hypertrophy induced by activation of intrinsic myocyte signaling. Activation of α1B adrenergic receptor-coupled signaling in the CA-α1B AR–overexpressing mouse caused a mild form of concentric left ventricular hypertrophy.17 Although the functional characteristics of these mice were not initially reported, there are no subsequent reports of contractile dysfunction. These findings are similar to homozygous mice overexpressing a myosin light chain-oncogenic ras fusion protein (MLC-ras) in which concentric left ventricular hypertrophy was associated with normal systolic function.25 A constitutively activated Gq-coupled receptor such as the α1BAR has the potential to activate, in addition to Gαq, other signaling pathways including those downstream of ras. Therefore the compensated hypertrophy of the CA-α1BAR–overexpressing mouse may most closely reproduce the phenotype of autocrine/paracrine mediated pressure-overload hypertrophy. In contrast, the Gαq and MLC-ras overexpressors represent hypertrophy that results from selective activation of distinct G-protein–coupled signaling pathways downstream of the receptor. Determining which myocardial signal transducers are differentially activated in Gαq and MLC-ras overexpressors has the potential to elucidate unique biochemical mechanisms for hypertrophy development and decompensation.
This study was supported in part by grants HL-49267 (G.W.D.) and HL-52318 (R.A.W., S.B.L., G.W.D., B.D.H.) from the National Institutes of Health, a Veterans Administration Merit Review Grant (G.W.D.), and the American Heart Association 1995 Council on Circulation Boots Cardiovascular Research Prize (G.W.D.). Dr Dorn is an Established Investigator of the American Heart Association. We gratefully acknowledge the work of Drew D D’Angelo, PhD, in constructing the Gαq transgenic mice, the technical assistance of Darryl Kirkpatrick in performing the isolated myocyte studies and Nancy Ball in performing the aortic banding surgery, and the secretarial assistance of Reene Cantwell.
- Received August 11, 1997.
- Revision received October 15, 1997.
- Accepted October 18, 1997.
- Copyright © 1998 by American Heart Association
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