(Hypertension. 1995;26:642-648.)
© 1995 American Heart Association, Inc.
Articles |
Apoptosis in Target Organs of Hypertension
Presented in part at the 14th International Society of Hypertension Congress, Melbourne, Australia, March 1994.
From the Centre de Recherche Hôtel-Dieu de Montréal, Université de Montréal (Canada).
Correspondence to Pavel Hamet, Laboratory of Molecular Pathophysiology, Centre de Recherche Hôtel-Dieu de Montréal, 3850 St. Urbain St, Montréal, Québec H2W 1T8, Canada.
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Abstract |
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Abstract Apoptosis or programmed cell death frequently parallels abnormalities in cell proliferation and differentiation. As hypertrophy/hyperplasia or remodeling occurs in organs affected by hypertension, we evaluated the degree of apoptosis in the heart, kidney, and brain in situ in genetically hypertensive mice and rats as well as in cultured vascular smooth muscle cells. Apoptosis was characterized by morphological features, DNA fragmentation, and laddering as well as by terminal deoxynucleotidyl transferase labeling of the 3' OH ends of both extracted DNA and tissue sections. The present report provides the first evidence of increased apoptosis in whole organs of genetically hypertensive rat and mouse strains: in the heart of spontaneously hypertensive rats (SHR) and in the heart (ventricular cardiomyocytes), kidney (inner cortex and medulla), and brain (cortex, striatum, hippocampus, and thalamus) of spontaneously hypertensive mice, with a higher effect of apoptotic inducers in cultured aortic smooth muscle cells derived from SHR. Both types of known apoptotic processes, oligonucleosomal cleavage and large DNA fragmentation, were observed in vascular smooth muscle cells, but only the former appeared to be increased in SHR. This study underlines the importance of cell death dysregulation in hypertension, reveals a new route for investigation of the pathogenesis of hypertension, and suggests novel targets of therapeutic intervention.
Key Words: apoptosis • hypertension • muscle, smooth, vascular • heart • kidney
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Introduction |
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Apoptosis is believed to be a predominant and ubiquitous physiological mode of cell death (for reviews, see References 1 and 21 2 ) distinct from the cell mortality induced by injury and necrosis. Generally, apoptosis is characterized by specific changes in the cytoplasm of cells, with fragmentation of chromatin resulting from cleavage by endonucleases at linker DNA sites between nucleosomes, which yields DNA fragments of multimers of 180- to 200-bp nucleosomal units while cell membranes remain preserved.3 4 5 This contrasts with necrosis, in which the plasma membranes of many adjacent cells are affected first. The term apoptosis is often used as a synonym of "programmed cell death" because both processes require the intervention of specific sets of genes, including c-fos, bcl-2, c-myc, and p53-ras.6 7 8 9 Apoptosis, or programmed cell death, has been extensively studied for its involvement in the immune response, tumor cell growth and regulation, and many other physiological processes, such as the development of cartilage, bone, gut, and remodeling of limb buds.10 11 12 13 Only a few studies have directed attention to the cardiovascular system. Programmed cell death has been demonstrated, for instance, in normal endothelial cells,14 and the cycle of growth, remodeling, regression, and decay has been documented in aortic endothelial cells15 and smooth muscle cells of the incisal artery during tooth development.16 Recently, deregulation of c-myc expression has been found to induce apoptosis in rat VSMCs.17
In hypertension, structural changes of vascular tissues may lead to rarefaction of the microvasculature, and electromicrographic characteristics of the microcirculation show many features that could in fact represent apoptosis. Although they did not specifically address the question of apoptosis, Baumbach and Heisted18 proposed the concept of VSMC remodeling in human and experimental hypertension that has been supported by other groups.19 20 The notion of capillary rarefaction in this disease was also introduced.21 We have recently postulated that the remodeling of cardiovascular tissues represents an imbalance between cell proliferation and apoptosis and that rarefaction may be a consequence of apoptosis.22 The present study evaluated this process in hypertension.
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Methods |
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In Vitro DNA Fragmentation
DNA fragmentation was evaluated in vitro in hearts or cultured aortic smooth muscle cells obtained from SHR and normotensive WKY and BN strains. Only male rats were used. They were killed at the ages specified in the figure legends. Aortic smooth muscle cells were cultured as described previously.23 The cells were treated and incubated as described in the figure legends. DNA was extracted from cell lysates (107 cells) in 200 µL buffer containing 20 mmol/L EDTA, 50 mmol/L Tris-HCl (pH 8.0), 0.5% SDS, and 0.5 mg/mL proteinase K; was incubated for 3 hours at 50°C; and was treated with RNase A (50 µL of 0.5 mg/mL for 1 hour at 37°C). After extraction with phenol and chloroform, DNA was precipitated, washed with 70% ethanol, and resuspended in Tris (10 mmol/L)/EDTA (1 mmol/L) buffer, pH 7.0. Ten micrograms was run on 1.5% agarose gel at 90 V for 3.5 hours and stained with ethidium bromide or labeled by tdt assay according to a slightly modified procedure24 of Gavrieli et al.25
Briefly, 1 µg of DNA extracted as above was labeled by enzymatic assay with the use of tdt in buffer containing 2 mmol/L CoCl2, 0.5 mmol/L dithiothreitol, 100 mmol/L potassium cacodylate, 166 mmol/L [32P]dCTP (3000 Ci/mmol), 664 mmol/L dCTP, and 20 U tdt. After incubation of the samples for 1 hour at 37°C, one tenth of this volume was loaded on a 1.5% agarose gel, run at 90 V for 3 to 5 hours, transferred onto a nylon membrane (Hybond N+, Amersham), exposed to a phosphor-sensitive screen, and analyzed with a PhosphorImager (Molecular Dynamics).
For quantification of DNA fragmentation, we used the protocol of Zacharchuk et al26 originally designed for T lymphocytes and adapted with minor modifications for VSMCs. VSMCs from 11 to 14 passages were cultured in 24-well plates in DMEM containing 10% calf serum, 100 U/mL penicillin, 100 µg/mL streptomycin, and 2 µCi/mL [3H]thymidine. The medium was aspirated after 24 hours, and the cells were washed twice with 2 mL PBS and then incubated for 48 hours in DMEM without [3H]thymidine and with 0.2% calf serum. The medium was again aspirated, and the cells were washed twice with PBS and 1 mL DMEM containing 0.2% calf serum without or with forskolin. After 18 to 20 hours the incubation medium (M) was collected for determination of radioactivity, and cells were transferred on ice and lysed with 1 mL ice-cold lysis buffer containing 10 mmol/L EDTA, 0.5% Triton X-100, and 10 mmol/L Tris-HCl (pH 8.0). After 15 minutes the cell lysates (S) were transferred into scintillation vials for the measurement of radioactivity (P). Intact chromatin attached to the cytoskeleton was solubilized with SDS (10%)/EDTA (4 mmol/L). After 10 minutes this mixture was collected for the determination of radioactivity. The relative levels of necrosis and apoptosis were calculated as 100xM/(M+S+P) and 100xS/(M+S+P), respectively.
In Situ Detection of DNA Fragmentation
In situ detection of apoptosis or DNA fragmentation was
performed on tissue sections of rats (SHR and WKY) or mice
(spontaneously hypertensive or normotensive) with an Apoptag kit
(Oncor) or as described elsewhere24 with the modifications
mentioned below. Hearts were collected and frozen in isopentane
(Fisher) at -18°C for 30 seconds. Sections (5 µm) were cut
with a cryostat, mounted on poly-L-lysine–coated
slides, fixed in 4% paraformaldehyde in phosphate
buffer for 30 minutes at room temperature, washed 3x15 minutes in PBS,
and steam-heated at 90°C for 30 minutes. The enzymatic reaction
was started by addition of, on the slide with the help of a coverslip,
30 µL of a solution containing 2 mmol/L CoCl2, 0.5
mmol/L dithiothreitol, 100 mmol/L potassium cacodylate, 30 mmol/L
Tris-HCl (pH 7.4), 0.05 mg/mL bovine serum albumin, 0.35 mmol/L
dATP, 50 nmol/L [32P]dCTP (3000 Ci/mmol), and 7 U tdt.
Nonspecific labeling was evaluated by omission of the enzyme. The
slides were incubated for 60 minutes at 37°C in a humidified
atmosphere; washed overnight in PBS containing 1% SDS at room
temperature, 2x30 minutes in PBS, and 20 seconds in H2O;
and air-dried. Finally, they were exposed against a
phosphor-sensitive screen and analyzed with the
PhosphorImager system.
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Results |
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Although DNA cleavage by Ca2+/Mg2+-dependent endonucleases into 180- to 200-bp fragments and their multiples is not always required for programmed cell death, it is a standard marker of apoptosis.27 We therefore searched for oligonucleosomal DNA accumulation in cells and organs of two genetic rodent models of hypertension. DNA analysis (10 µg) on ethidium bromide–stained gel revealed similar amounts of intact DNA but with increased DNA degradation in cultured VSMCs from SHR under basal culture conditions and after the addition of TGF-ß1 or pentoxifylline compared with normotensive BN controls (data not shown). The labeling of DNA breaks and small fragments was amplified because of greater accessibility of the 3' OH ends.28 We thus used a technique similar to that of Gavrieli et al25 for labeling of DNA cleavage with tdt. Fig 1A illustrates that from equal amounts of deposited DNA (100 ng), labeled oligonucleosomal DNA laddering typical of apoptosis was clearly visible in SHR VSMCs, whereas it was absent or weak in BN VSMCs. The addition of 500 U/mL TNF-
strongly diminished DNA fragmentation in
SHR VSMCs, but its inhibitor, pentoxifylline (200 µg/mL)
and TGF-ß1 (5 µg/mL), accentuated apoptosis in
these cells (Fig 1A and 1B).
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It has recently been recognized29 30 that an early or parallel type of DNA fragmentation occurs at DNA nuclear matrix cleavage sites. In VSMCs, large DNA fragments were generated in parallel to oligonucleosomal cleavage (Fig 1A, a). The importance of large DNA fragments relative to oligonucleosomal cleavage may vary with the apoptotic inducer or inhibitor. Quantification of small-size DNA oligonucleosomes (from 180 to 1500 bp) (Fig 1A, b) showed a significant (P<.05) increase of DNA fragmentation in serum-deprived SHR cells (induced by a change from 5% to 0.5% calf serum), with a further increase (P<.01) after pentoxifylline treatment when compared with normotensive cells (Fig 1B). The addition of 5 µg/mL actinomycin D abolished apoptosis in both cell types (not shown).
The difference in apoptosis between SHR and BN VSMCs in low
serum (0.5%) was also visualized by light microscopy (Fig 2, A and B). When apoptosis was
induced in both cell lines by the addition of 200 µg/mL
pentoxifylline, it was clearly more evident in SHR VSMCs (Fig 2, C versus D). Pentoxifylline, a methylxanthine
derivative, has been shown to effectively inhibit TNF- mRNA
accumulation, apparently through cAMP-dependent suppression of the
TNF- gene transcription rate.31 Since cAMP may play a
role in apoptosis, we treated VSMCs with a ß-adrenergic
agonist, isoproterenol. Table 1 shows that isoproterenol
significantly increased both cAMP production and DNA
fragmentation, with higher increments in SHR versus BN VSMCs. It is
therefore possible that in hypertensive animals apoptosis is
enhanced via cAMP-mediated processes in concordance with higher
agonist-induced cAMP increases early in
hypertension.33 Table 1 reveals that the apoptotic
process does not proportionally follow cAMP levels, suggesting that
their relationship is complex. This suggestion is supported by data on
DNA fragmentation in [3H]thymidine-labeled VSMCs.
Table 2 demonstrates that the percentage of
apoptosis (the relative amount of radioactivity in cell lysates
supernatant) after 48 to 68 hours of VSMC incubation in medium
containing 0.2% calf serum was about 4% in both SHR and BN VSMCs. In
contrast to isoproterenol, forskolin-induced cAMP
production was not different between VSMCs from SHR and BN.
Forskolin did not significantly alter DNA fragmentation in BN but
doubled apoptosis in SHR VSMCs. This study also indicates that
necrosis (represented by the relative amount of
radioactivity in the incubation medium) was not different between BN
and SHR and was unaffected by forskolin.
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With progressing hypertension, the heart, aorta, kidney, and brain are the main targets of damage. In a significant proportion of patients hypertension-induced left ventricular hypertrophy is a major cardiovascular risk factor for mortality from this disease.34 Although proliferative changes also occur in the kidney, the brain of hypertensive patients before the advent of effective pharmacological treatment often manifested status lacunaris as evidence of cortical damage. To evaluate apoptosis in these target organs, we have developed an assay for in situ tdt labeling of tissue slices24 in which the density of labeling corresponds to the amplification of oligonucleosomal DNA fragments. The amount of DNA fragments is determined in whole tissue sections by PhosphorImager densitometry.24 This novel approach allows quantification of apoptosis in anatomically and functionally distinct areas. In SHR, an increase of apoptosis is observed in the ventricular portion of the heart at 8 (Fig 3, left) and 16 weeks of age compared with age-matched normotensive WKY controls.22 Although not evenly distributed in this organ, apoptosis is clearly increased in the SHR heart. Labeling is not seen when tdt is omitted (control without enzyme). To examine whether the labeling visible in tissue sections is really caused by internucleosomal DNA fragmentation and not by variations in organ DNA content, we extracted DNA from the heart of these rats and labeled it in vitro. The results shown in Fig 3 (right) demonstrate oligonucleosomal laddering in DNA extracted from the heart of 8-week-old SHR but not in age-matched normotensive WKY controls, confirming data obtained by the in situ labeling technique. Again, as was the case in vitro, both oligonucleosomal and large-type DNA fragmentation were observed in vivo, with only the former being clearly increased in SHR. In the context of well-described cardiac hypertrophy, we noted a 40% to 50% increase in the ratio of heart weight to body weight in 16-week-old SHR compared with WKY (P<.02). At this age, the level of apoptosis was increased 2.6-fold in the SHR heart relative to WKY controls: mean net apoptosis (after the density of heart slices in the absence of tdt enzyme was subtracted) was 398±144 in WKY and 1058±165 pixel · V-1 · h-1 in SHR (n=4, slices obtained from three different animals for each species; P<.01).
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Since the appropriate control strain for genetically based hypertension is often disputed,35 we studied an unrelated normotensive BN strain in addition to WKY controls.36 The data reported indicate increased apoptosis in cultured SHR VSMCs and hearts compared with these two normotensive rat strains. We have previously discussed the importance of confirming pathogenetic observations in distinct hypertensive rodent species to verify the possibility of primary involvement in the pathology of genetically defined hypertension.37 We thus investigated the spontaneously hypertensive mouse model developed by Schlager.38 This model was engineered by an eight-way cross of inbred strains from Jackson Laboratories by selecting hypertensive and normotensive populations, followed by a period of stabilization of the expression of hypertension, and only then was completed by full inbreeding. Fig 4 shows apoptosis in the organs of 1-year-old hypertensive (untreated) mice (right) compared with normotensive controls (left). It is evident that although the atria appear unaffected, there is apoptosis in the heart ventricle (Fig 4A and 4E). In the kidney, apoptosis is visible in the inner part of the cortex and in the medulla (Fig 4B and 4F), and the most affected areas in the brain include the cortex, striatum, hippocampus, and thalamus (Fig 4C and 4G). Our findings may be of interest because a decrease in cell size and density has already been reported in these brain regions in SHR.39 In fact, neuronal loss could be the origin of hyperactivity in hypertensive rats.40 Alternatively, apoptosis in the brain may affect capillaries in these regions. In contrast, no strong evidence of apoptosis is found in the skeletal muscles of both hypertensive and normotensive mice (Fig 4D and 4H). Although it would be worthwhile to verify the possibility that rarefaction occurring in the microvasculature of muscles21 could be caused by apoptosis, the method used here does not have the discriminative power to selectively evaluate capillaries.
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To identify the type of cells undergoing apoptosis, we performed in situ DNA end-labeling in organ sections with tdt and digoxigenin-nucleotide (Apoptag kit, Oncor). Fig 5 shows that apoptosis occurs in cardiomyocytes of the hypertensive mouse heart (Fig 5A and 5B). In the hypertensive mouse kidney apoptosis is seen in the glomeruli (Fig 5D), and the cell types involved are mainly epithelial cells and some mesangial cells (Fig 5C).
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Discussion |
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The increased proliferation of VSMCs and cells in other target organs of hypertension occurs in vivo41 from the neonatal stage27 42 and persists in culture.23 43 44 45 We have shown here that this well-described increase in proliferation is in fact paralleled by apoptosis in hypertensive strains and even in culture. Several other general features of the apoptotic process are also distinctive traits of cultured VSMCs from hypertensive rats, including abnormalities in the response or accumulation of TGF-ß1,46 47 48 49 TNF,50 51 and cAMP signaling (Table 1)52 53 54 55 as well as heat-shock protein 70 gene product accumulation.56 57 Growth anomalies related to defective monovalent and divalent ion transport are hallmarks of hypertension.58 59 In hypertensive humans and genetic models of hypertension, Na+-H+ antiporter activity is increased,59 60 with bimodal distribution61 caused by augmented activity of the ubiquitous isoform of the Na+-H+ exchanger. In this respect, recent data reported by Cáceres-Cortés et al62 are noteworthy because they include this antiporter in the apoptosis regulatory pathway. The apoptotic process may be involved in remodeling of cardiovascular organs even though some of them, such as the heart, are believed to have a finite number of functional cells.
We have now demonstrated that apoptosis is an initial step to cardiac hypertrophy induced by aortic stenosis (unpublished observations, 1995). Two important notions arise from this work: (1) Apoptosis, although present in nonmuscular cells of the myocardium in a basal state, is induced selectively in cardiomyocytes after acute hemodynamic stimulation. (2) Apoptosis occurs in the initial phase of the hypertrophic process and is of short duration, clearly preceding and then fading at the time of cardiac hypertrophy. We suggest that it may therefore be involved in cardiac remodeling, but further studies are required for determination of whether it is a prerequisite for cardiac remodeling or whether hypertrophy represents a failure of compensatory apoptosis.
In the present study we have shown that oligonucleosomal DNA fragments are increased both in vivo and in vitro in SHR. In addition, a more recently recognized type of large DNA fragmentation in apoptosis is also seen in vitro and in vivo in VSMCs and the heart. This type a cleavage,29 30 63 found at the scaffold protein DNA attachment point, may occur before or in parallel with oligonucleosomal cleavage (type b). The exact type of nucleases and their respective control and role in the apoptotic process are presently being uncovered, but new protein synthesis is required for apoptosis in VSMCs, as is the case in other cell types.63 Although necrosis appears to affect 4% of VSMCs in culture, it is unchanged by serum withdrawal or agonist stimulation. Apoptosis, when induced by a cAMP-generating agent, is selectively doubled in SHR VSMCs, involving 8% of cells.
Our studies reveal for the first time a higher level of
apoptosis in organs and cultured cells from genetically
hypertensive rodents. Thus, increased cell mortality, typical of
programmed cell death, accompanies the hypertrophy and
hyperplasia of cardiovascular organs in hypertension.
The mechanism of heightened susceptibility to apoptosis may
involve TGF-ß1, TNF-, cAMP, or other pathways.
The exact apoptotic pathway and the relative importance of
oligonucleosomal versus large-fragment DNA cleavage, which may be
genetically altered in hypertension, are to be investigated. These
observations establish a new way of studying the pathogenesis of
hypertension and its consequences. They should foster a reevaluation of
therapeutic interventions in hypertension, not only at the level of
cell proliferation but also of apoptosis, its essential
counterpart.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This work was supported by a grant from the Medical Research Council of Canada (MT-10803) and by Bayer Canada. J.T. is a scholar from Fonds de la Recherche en Santé du Québec. The authors are grateful for the constructive comments of Drs Luc Villeneuve and Drahomira Krenova and for review of this manuscript by Drs Vladimir Kren, Yu-Lin Sun, Trang Hoang, and Richard Bertrand. The secretarial assistance of Josée Bédard-Baker and the editorial help of Ovid Da Silva are appreciated.
Received May 8, 1995; first decision May 30, 1995; accepted May 30, 1995.
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