(Hypertension. 1995;26:1149-1153.)
© 1995 American Heart Association, Inc.
Articles |
Basal and Angiotensin II–Induced Cytosolic Free Calcium in Adult Rat Cardiomyocytes and Fibroblasts After Volume Overload
From the MRC Multidisciplinary Research Group on Hypertension, Clinical Research Institute of Montreal, University of Montreal (Canada).
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Abstract |
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Abstract This study investigates basal and angiotensin II (Ang II)–induced [Ca2+]i concentrations in cells from hearts of rats that have undergone cardiac hypertrophy due to volume overload. [Ca2+]i measurements assessed by digital imaging using fura 2 methodology were performed on isolated ventricular cardiomyocytes and fibroblasts from adult rat hearts with a 4-week aortocaval shunt. Long-term aortocaval shunt induced a significant increase in atrial (72%) and ventricular (41%) weights and a large elevation in plasma atrial natriuretic peptide-(1-98) concentration (160%). For adult cardiomyocytes [Ca2+]i measurements are reported as diastolic (average of the lowest points) and systolic intracellular Ca2+ values (average of the maximum points corresponding to the diastolic points) over a 30-second time interval. Basal diastolic [Ca2+]i (99±4.1 nmol/L for experimental cells versus 90±4.8 for control cells) was not altered, whereas basal systolic [Ca2+]i was significantly greater in ventricular cardiomyocytes from overload hearts (155±2.3 versus 129±4.4 nmol/L for control cells, P<.05). Ang II increased intracellular Ca2+ spike frequency in a concentration-dependent manner in cardiomyocytes from control and overload myocardium. Basal and Ang II–induced intracellular Ca2+ spike frequencies were not modified in cardiomyocytes from hypertrophied hearts. Basal [Ca2+]i in ventricular fibroblasts from overload myocardium was significantly increased (128±5.1 nmol/L for fibroblasts from hypertrophied hearts versus 104±3.5 for control cells, P<.05). Ang II–induced [Ca2+]i was lower in fibroblasts from overload myocardium (P<.05). In conclusion, alterations of intracellular calcium homeostasis in the two predominant cardiac cell types involved in myocardial growth and fibrosis, cardiomyocytes and fibroblasts, respectively, may contribute to the physiopathology of heart failure in adult rats. Ang II signaling through the intracellular calcium transduction pathway in a cell-specific manner may play an important role in cardiac hypertrophy.
Key Words: angiotensin II • myocardium • fibroblasts • calcium • heart hypertrophy
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Introduction |
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Cardiac hypertrophy is a compensatory response to volume or pressure overload of the myocardium. Increased cardiac load stimulates cell growth, protein synthesis, transcriptional levels of proto-oncogenes and fetal genes,1 and fibrosis.2 Adaptive cardiac hypertrophy is associated with remodeling of cardiomyocytes,3 changes in vascular and interstitial compartments,2 and alteration of cardiac performance,3 which may lead to congestive heart failure. However, the mechanisms underlying the transition to heart failure remain to be elucidated. It is well established that free calcium concentration is directly involved in cardiac excitation-contraction coupling and plays a central role in intracellular signaling pathways. Altered intracellular calcium handling is associated with the development of myocardial dysfunction.4 However, most previous studies investigating changes in cell calcium release have been performed on intact cardiac muscle and ventricular papillary tissue5 6 ; few studies are available on isolated cardiac cells.7 8
Ang II is a potent vasoactive peptide that acts directly and indirectly at various levels on the cardiovascular system. Ang II has direct inotropic, chronotropic, and growth actions on the myocardium.9 Two distinct Ang II receptor subtypes, AT1 and AT2, are well identified in various tissues, including the heart.10 It is well known that the AT1 receptor mediates most Ang II actions on vascular and myocardial tissues.11 In contrast, the physiological role of the AT2 receptor, which is highly expressed in the embryonic and neonatal states, remains to be elucidated. The detection of the expression of angiotensinogen and angiotensin-converting enzyme gene in the myocardium suggests the existence of a local intracardiac renin-angiotensin system.12 Although the heart is composed of two predominant cell types, cardiomyocytes and fibroblasts, that respond differentially to growth factors or cardiac overload, most previous studies have been performed on intact myocardium. Indeed, Ang II was found to cause hypertrophy in cardiomyocytes and hyperplasia in cardiac nonmyocyte cells or fibroblasts.13 The trophic effects of Ang II are mediated by the AT1 receptor subtype.3 13 14
Intracellular pathways underlying Ang II actions lead to the production of water-soluble inositol phosphates and diacylglycerol, which induce an increase in [Ca2+]i and protein kinase C activation, respectively. Ang II stimulates directly inward Ca2+ currents in neonatal cardiomyocytes.15 Chronotropic, inotropic, and cardiac growth effects of Ang II on cardiomyocytes have been shown to be mediated mainly by phospholipase C and intracellular calcium modulation.16 17 Little information on cytosolic calcium regulation in cardiomyocytes and nonmyocyte cells from hypertrophied hearts is available.7 8 In the present study we investigated basal [Ca2+]i and the effects of Ang II on intracellular calcium response changes in adult ventricular cardiomyocytes and fibroblasts from volume-overload hypertrophied myocardium resulting from an aortocaval shunt in adult rats. This experimental model is well known to induce a lower mean arterial pressure and higher right atrial and left ventricular end-diastolic pressures associated with a marked cardiac hypertrophy in aortocaval shunt compared with sham-operated rats.18
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Methods |
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Animals and Aortocaval Shunt Surgery
Male Sprague-Dawley rats (200 to 220 g; Charles River, St Constant, Quebec, Canada) were used. The protocol was in accordance with the guidelines of the Canadian Council on Animal Care. The surgical procedure to induce volume overload by an aortocaval shunt has been previously described.18 Sham-operated rats (control group) were subjected to the same surgical procedure with no vessel puncture. Four weeks after cardiac volume overload the rats were killed.
Adult Cardiomyocyte Isolation
Rats were first injected intraperitoneally
with 500 U heparin sulfate (Hepalean, Organon Canada Ltd) and
anesthetized with pentobarbital sodium (60 mg/kg IP). The heart
was rapidly removed. Calcium-tolerant cardiomyocytes
were isolated by cardiac retrograde aortic perfusion (Langendorff
method) as described previously.19 Freshly isolated cells
were gently diluted in sterile culture M199 medium, pH 7.4, with 10%
fetal bovine serum. The culture medium (M199) was supplemented with
0.2% bovine serum albumin, 10-7
mol/L insulin, 5 mmol/L creatine, 2 mmol/L L-carnitine, 5
mmol/L taurine, 100 IU/mL penicillin, and 100 µg/mL streptomycin.
Ventricular cells were seeded onto round glass coverslips
in culture dishes (7000 cells per 2 cm2) that had been
coated previously with laminin for 1 hour at room temperature (3 µg/2
cm2, Collaborative Research Inc). After 1 hour at
37°C (in an incubator humidified with 5% CO2/95%
air) the medium was changed to remove damaged cells
(globular-shaped cells) and debris. We obtained 90%
calcium-tolerant cardiomyocytes (rod-shaped cells)
or 2x106 to 2.5x106 cells per
heart, which corresponds to greater than 95% cardiomyocyte
purity. Serum-free medium was added overnight, and
[Ca2+]i measurements were performed
the following day.
Primary Culture of Adult Ventricular
Fibroblasts
Rats were injected with heparin sulfate and pentobarbital. After
cardiac dissection ventricles were removed from atria and large vessels
and washed in sterile 0.05 mol/L sodium phosphate with 0.9 g/dL NaCl.
They were finely minced and digested in 15 mL Dulbecco's modified
Eagle's medium containing 0.1% trypsin and 100 U/mL
collagenase (CLS2, Worthington Biochemical Corp) at
37°C with agitation (150 cycles per minute) for 15 minutes as
previously described.14 Cells were incubated for 2 hours
at 37°C in a 10% CO2/90% air–humidified
incubator. After the preplating step nonadherent cells were removed,
and fresh serum medium was added. The remaining cells (mostly
fibroblasts) were grown until confluence (4 to 5 days, approximately
2x105 cells per 2 cm2). Twenty-four hours
before [Ca2+]i assays, culture medium
was replaced by serum-free medium.
Radioimmunoassays [ANP-(1-98)]
Blood was collected in ice-chilled tubes containing EDTA and
pepstatin and centrifuged at 1500g for 10 minutes at
4°C for determination of plasma ANP-(1-98) concentrations as
previously described.20
Measurements of [Ca2+]i
[Ca2+]i measurements were
performed with fura 2 methodology.19 21 Adult
cardiomyocytes and fibroblasts were loaded with 4 µmol/L
fura 2–AM for 30 minutes at 37°C in an incubator humidified with
95% air/5% CO2 and washed three times with modified
Hanks' buffer containing (mmol/L) NaCl 137, NaHCO3 4.2,
NaHPO4 3, KCl 5.4, KH2PO4 0.4,
CaCl2 1.3, MgCl2 0.5, MgSO4 0.8,
glucose 10, and HEPES 5 (pH 7.4). Fluorescence measurements
were assessed with the use of double excitatory wavelengths (343 and
380 nm) and a single emission wavelength (510 nm).19 22
[Ca2+]i was measured in isolated cells
by microphotometry and in cell clusters by fluorescent digital
imaging, and microphotometric [Ca2+]i
results were comparable to those obtained from digital imaging
analysis (basal and stimulated cells).
[Ca2+]i was calculated according to
the formula of Grynkiewicz et al,23 where the dissociation
constant for fura 2–Ca2+
(Kd) was taken to be 224 nmol/L.
Fluorescence experiments were performed with the Axiovert 135
inverted microscope and Attofluor digital fluorescence system
(Zeiss). After an equilibration period cultured cells were exposed to
single concentrations (50 µL) of Ang II
(10-12 to
10-4 mol/L) at room temperature. The
maximal peak ratio recorded corresponded to the maximal response of
the agonist. [Ca2+]i determinations
were performed on cardiac cells from control and hypertrophied hearts
(50 to 75 cells).
Statistical Analysis
All data are reported as mean±SEM. Plasma ANP-(1-98)
concentration assays were performed on 10 rats per group and
[Ca2+]i experiments on five rats per
group. Statistical significance between shunt and sham-operated
rats was determined with the unpaired Student's t test.
[Ca2+]i measurements were compared by
ANOVA for repeated measures or by Student's t test as
appropriate. The significance level was set at a value of
P<.05.
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Results |
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Body and Heart Weights and Plasma ANP Concentration
Long-term cardiac volume overload induced by aortocaval shunt did not cause any change in rat body weight (374±12 versus 366±10 g for control rats). Shunt rats demonstrated cardiac hypertrophy, as observed by significant increases in the relative weight of atria (31±1 versus 18±0.7 mg/100 mg body wt for sham-operated rats, P<.001) and ventricles (371±13 versus 263±6 mg/100 mg body wt for control rats, P<.001). Plasma ANP-(1-98) was significantly higher in aortocaval shunt rats (1250±118 versus 485±51 fmol/mL for sham-operated rats, P<.001).
Basal and Ang II–Induced [Ca2+]i
in Cardiomyocytes From Control and Hypertrophied Hearts
In resting and stimulated states calcium-tolerant
cardiomyocytes are characterized by spontaneous contractile
waves corresponding to calcium release and contractile
activity.19 Consequently, cardiomyocyte
[Ca2+]i measurements are reported as
diastolic and systolic
[Ca2+]i values (in nanomoles per
liter). Diastolic [Ca2+]i
was determined as the average of the lowest point of each tracing over
a 30-second period, and systolic
[Ca2+]i was taken as the average of
the maximum points. The frequency of the
[Ca2+]i spike was defined over a
60-second time interval (spikes per minute). Basal
diastolic and systolic values in adult
cardiomyocytes from control and hypertrophied
myocardium are presented in Fig 1.
Long-term volume overload induced no alteration in
diastolic [Ca2+]i (99±4.1
versus 90±4.8 nmol/L for control cells), whereas systolic
[Ca2+]i was significantly higher in
cardiomyocytes from overload myocardium
(155±2.3 versus 129±4.4 nmol/L for control cells, P<.05).
Consequently, [Ca2+]i amplitude was
significantly greater in cardiomyocytes from overload
myocardium (56±4.2 versus 39±3.5 nmol/L for control
cells, P<.05). In the basal state
[Ca2+]i spike frequency was unchanged
in cardiomyocytes from hypertrophied myocardium
(Fig 2). Cardiac volume overload may
enhance inotropy by increasing [Ca2+]i
transients and may not modify chronotropy in adult
cardiomyocytes from hypertrophied hearts.
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To determine Ang II effects on [Ca2+]i transients and spike frequencies in adult cardiomyocytes from hypertrophied hearts, we studied the capacity of Ang II to stimulate [Ca2+]i in isolated control and experimental cells. In control conditions Ang II increased [Ca2+]i spike frequency in a concentration-dependent manner (Fig 2). The Ang II–induced [Ca2+]i response was higher in cardiomyocytes from overload myocardium compared with control cells (Fig 1). Exposure to 10-5 mol/L Ang II, which provides a maximal response (EC100), or to an Ang II concentration giving 50% of the maximal response (EC50) significantly increased diastolic and systolic [Ca2+]i in cells from hypertrophied myocardium (Fig 1, P<.01). Consequently, the [Ca2+]i amplitude increase induced by 10-5 mol/L Ang II or by an Ang II concentration giving 50% of the maximal response was significantly greater in cardiomyocytes from hypertrophied hearts (125±11 versus 72±9 nmol/L for EC100, hypertrophied cells versus control cells, P<.01; 126±7 versus 45±5 nmol/L for EC50, hypertrophied cells versus control cells, P<.01). Ang II–induced [Ca2+]i spike frequency, however, was unchanged in cardiomyocytes from overload myocardium (pD2, 7.5±0.1 for experimental cells versus 7.25±2.6 for control cells; Fig 2). Ang II may have an inotropic effect by increasing [Ca2+]i transients (diastolic and systolic values) at low and high Ang II concentrations but did not modify the beating frequency of cardiomyocytes from overload hearts.
Basal and Ang II–Induced [Ca2+]i
in Cardiac Fibroblasts From Control and Hypertrophied
Hearts
Ventricular fibroblasts do not present any
spontaneous contractile waves in the resting and stimulated states as
previously reported.19 Basal
[Ca2+]i was significantly higher in
cardiac fibroblasts from overload hearts (128±5.1 versus 104±3.5
nmol/L for control cells, P<.05). As shown in Fig 3, at a high Ang II concentration
(10-5 mol/L)
[Ca2+]i was significantly reduced in
cardiac fibroblasts from hypertrophied hearts compared with control
cells (P<.05). Similarly, the Ang II concentration giving
50% of the maximal response (EC50) decreased
[Ca2+]i significantly
(P<.05).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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This study demonstrates that in primary cultured cardiomyocytes and fibroblasts from hypertrophied hearts basal cytosolic calcium was significantly increased, suggesting that after cardiac volume overload intracellular calcium homeostasis is altered. In this condition volume overload may enhance contractility by increasing the systolic [Ca2+]i of cardiomyocytes from hypertrophied myocardium. Moreover, enhanced Ang II [Ca2+]i transients in cardiomyocytes from overload hearts and attenuated [Ca2+]i responses in fibroblasts from hypertrophied hearts suggest that Ang II–induced [Ca2+]i responses are regulated in a cell-specific manner in cardiac cells after cardiac volume overload, probably because both cell types respond differentially to cardiac overload, ie, cardiomyocyte enlargement3 and fibroblast proliferation.2
Adult rat cardiomyocytes and cardiac fibroblasts in culture provide us with the opportunity to study in vitro the mechanisms of cardiac hypertrophy leading to heart failure. In the present study the morphological appearance, biochemical markers, and cell-specific intracellular calcium response demonstrate a high level of purity of the cell preparation used,19 allowing the behavior of signal transduction in cardiomyocytes and fibroblasts to be investigated individually. Various studies have demonstrated that in the spontaneously hypertensive rat, basal [Ca2+]i is increased in various cell types, such as vascular smooth muscle cells21 and platelets.24 In contrast to these, basal [Ca2+]i transients were decreased6 7 or increased25 in hypertrophied myocardium. The reason for these conflicting reports may be attributable to the fact that these investigations were conducted on different species. In the present study cytosolic free calcium in the basal state was increased in cardiomyocytes (only systolic) and in fibroblasts from hypertrophied rat hearts. Cytosolic calcium increase may be closely correlated to the adaptive events of cardiac hypertrophy such as protein synthesis and cell growth.1 4 We report for the first time that cytosolic free calcium was increased in cardiac fibroblasts from hypertrophied hearts, suggesting that the enhancement of the intracellular calcium pathway may have a role in the mitogenic response and trophic phenotype in nonmyocyte cells in cardiac hypertrophy. Elevated intracellular calcium can be explained by abnormalities of cellular calcium mobilization previously observed in myocardial dysfunction.4 Reduced Ca2+ channel number and depressed Ca2+ pump activity have been demonstrated in plasma membranes of hypertrophied rat hearts.25 Also, a decrease in intracellular calcium stores has been reported.5 However, the exact mechanism by which basal [Ca2+]i increased in response to volume overload remains to be elucidated. In cardiomyocytes from hypertrophied hearts systolic [Ca2+]i was increased, with no change in the diastolic [Ca2+]i value, and consequently the amplitude of the [Ca2+]i transients was increased by 43%, which could result in enhanced contractility in hypertrophied cardiomyocytes. In contrast, Meggs et al3 reported depressed left ventricular contractile performance in cardiomyocytes from pressure-overload hypertrophy. The discrepancy in contractile function between the studies may be related to differences in the time period and model used to induce cardiac hypertrophy. Myocardial abnormalities due to cardiac hypertrophy may also be related to the development of apoptosis in the myocardium.26
Ang II increased in a concentration-dependent manner the [Ca2+]i spike frequency and had no significant effect on [Ca2+]i transients at a physiological concentration in normal adult cardiomyocytes,19 a finding in agreement with the positive chronotropic effect and the lack of inotropic action of Ang II previously demonstrated in adult rat cardiomyocytes.9 Cardiac volume overload may result in enhanced Ang II inotropic effects in adult cardiomyocytes from overload myocardium, because Ang II was able to increase significantly the diastolic and systolic [Ca2+]i transients. In contrast, the chronotropic effect of Ang II was not altered in cardiomyocytes after cardiac volume overload. Such adaptation may explain the impairment in contractile function demonstrated in hypertrophied cardiomyocytes.3 Ang II–induced contractility is cell surface receptor mediated exclusively by the AT1 subtype.11 It is well established that ventricular Ang II receptors are developmentally regulated, with an elevated number of Ang II binding sites in the neonatal period and a subsequent decrease with maturation,27 28 which suggests that cardiac Ang II receptors may play a role in cardiac development.12 In pathophysiological hypertrophic changes, cardiac Ang II receptors and Ang II–induced phosphoinositide turnover were significantly increased,3 29 indicating that cardiac Ang II receptors and the intracellular second messenger pathway are pathologically upregulated. Together with the results of previous studies the present enhancement of Ang II responsiveness of [Ca2+]i transients in cardiomyocytes from hypertrophied hearts suggests that cardiac Ang II receptors3 and associated intracellular pathways may reappear in pathological myocardium resembling the embryonic state.
Various studies provide evidence that Ang II cell surface receptors are exclusively of the AT1 subtype in cardiac fibroblasts.13 14 30 However, few data on the intracellular signaling pathway in cardiac fibroblasts from overload myocardium are available. To our knowledge we report for the first time the Ang II–induced calcium handling in adult fibroblasts from control and hypertrophied hearts. The lower Ang II–induced calcium response in fibroblasts from overload myocardium is in agreement with downregulation of 42% of AT1 receptor density on cardiac fibroblasts after cardiac volume overload (unpublished data, 1995). Cardiac pressure overload induced an abnormal collagen accumulation with increased myocardial stiffness, whereas long-term volume overload caused a decrease in collagen deposition in left ventricles.2 Thus, from the present study the attenuation of Ang II effects on the intracellular signaling pathway observed after volume overload may be involved in adaptive trophic mechanisms other than fibrosis.
In conclusion, the present study shows that basal [Ca2+]i was significantly higher in cardiomyocytes and fibroblasts from hypertrophied hearts. Systolic [Ca2+]i was greater in cardiomyocytes from overload hearts, which may underlie enhanced contractility, whereas [Ca2+]i spike frequency was not altered. Cardiac volume overload induced an enhanced responsiveness of [Ca2+]i transients to Ang II in cardiomyocytes, whereas Ang II–induced [Ca2+]i response was lower in fibroblasts, indicating that the Ang II signal transduction pathway is regulated in a cell-specific manner in the myocardium. Ang II through the calcium signal transduction pathway may play an important role in the pathophysiology of cardiac hypertrophy.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This work was supported by a group grant to the Multidisciplinary Research Group on Hypertension from the Medical Research Council of Canada (MRC) and grants from the Fondation des maladies du coeur du Québec. Drs J. Fareh and R.M. Touyz are recipients of fellowships from the Canadian Hypertension Society/MRC and the MRC, respectively.
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Footnotes |
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Reprint requests to Gaetan Thibault, PhD, Clinical Research Institute of Montreal, 110 Pine Ave West, Montreal, Quebec, H2W 1R7, Canada. E-mail thibaug@ircm.umontreal.ca.
Received June 19, 1995; first decision August 23, 1995; accepted September 9, 1995.
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