ACLS
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Hang, T.
Right arrow Articles by Ren, H.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Hang, T.
Right arrow Articles by Ren, H.
Annals of Clinical & Laboratory Science 36:88-95 (2006)
© 2006 Association of Clinical Scientists

Apoptosis in Pressure Overload-Induced Cardiac Hypertrophy Is Mediated, in Part, by Adenine Nucleotide Translocator-1

Tao Hang1,2, Zhaoqi Huang1, Shisen Jiang2, Jianbin Gong2, Chunhui Wang2, Dujiang Xie2 and Hailing Ren2
1 School of Life Science, Nanjing University, and 2 Department of Cardiology, Jinling Hospital, Nanjing, People’s Republic of China

Address correspondence to Tao Hang, Ph.D., Department of Cardiology, Jinling Hospital, 305 East Zhongshan Road, Nanjing 210002, P.R.China; tel 86 25 8086 0880; fax 86 25 8459 5315; e-mail: njht1976{at}yahoo.com.cn.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
This study explored the role of adenine nucleotide translocator-1 (ANT1) in cardiomyocyte apoptosis during left ventricular hypertrophy (LVH) that developed in response to pressure overload. Pressure overload was induced surgically in 21 male Sprague-Dawley rats by thoracic aortic constriction at 12 weeks of age. An equal number of sham-operated, age-matched male rats served as controls. Aortic blood pressure (ABP), LVH, myocardial apoptosis index (MAI), and ANT1 mRNA expression were quantified in 7 subgroups of 3 treated and 3 control rats that were killed, respectively, at 1, 2, 4, 7, 14, 21, or 30 days post-surgery. Compared to controls, ABP increased gradually throughout the study in the treated rats with aortic coarctation; LVH did not develop significantly until 4 days post-surgery and increased progressively afterwards. The myocardial apoptosis index (assayed by TUNEL-labeling) increased immediately post-surgery, reached a plateau from 4 to 7 days, and then declined rapidly; apoptosis was undetectable throughout the study in cardiomyocytes of control rats. In treated rats, the expression of ANT1 mRNA in myocardium was up-regulated at 4 days, peaked at 7 days, and returned to control levels at 14 days post-surgery. These findings suggest that (i) apoptosis of cardiomyocytes is an important regulatory mechanism that is involved in the cardiac adaptive response to pressure overload, and (ii) the apoptosis of cardiomyocytes is mediated, in part, by ANT1.

Keywords: adenine nucleotide translocator-1, apoptosis, cardiac hypertrophy, hypertension


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
An increase in imposed cardiac workload promotes an adaptive response of cardiac hypertrophy. This response is initially compensatory, whereas prolonged cardiac overload leads to decreased cardiac function and eventually to heart failure. The mechanisms underlying the initial compensatory hypertrophy have not been thoroughly elucidated, although clinical and experimental studies suggest that inhibition of angiotensin-converting enzyme and angiotensin II receptor blockade promote the regression of cardiac hyper-trophy due to pressure overload [1–3]. Among several mechanisms involved in hypertensive heart disease, a critical role is played by apoptosis [4]. Because cardiomyocytes are non-dividing cells, cardiac apoptosis leads to decreased numbers of cardiomyocytes and the lost cells are replaced by fibrous tissues. This causes the workload on the remaining cardiomyocytes to increase and consequently induces compensatory cardiac hypertrophy. The induction of apoptosis is governed by an elaborate system of checks and balances in the cell. In vitro studies have demonstrated that mitochondria are required for the apoptosis induced by a variety of different factors [5], and that adenine nucleotide translocator (ANT) may play a pivotal role in the process [6].

ANT, one of the most abundant mitochondrial proteins, is localized on the inner mitochondrial membrane (IM) and exchanges cytosolic ADP for mitochondrial ATP [7]. Three ANT isoforms exist in humans and 2 in rodents; the ANT isoforms are expressed in a tissue-specific fashion. For instance, in rats and mice, ANT1 is primarily expressed in heart and skeletal muscle, whereas isotype ANT2 is expressed in all tissues [8].

ANT interacts with several proteins of the mitochondrial outer membrane (OM) (eg, peripheral benzodiazepine receptor, voltage-dependent anion channel (VDAC), and Bax), as well as a matrix protein (cyclophilin D), to form the permeability transition pore (PTP) in the IM/OM contact site [9–11]. The PTP appears to be an important regulator of apoptosis. Opening of the pore leads to loss of mitochondrial transmembrane potential ({Delta}{psi}m), which can culminate in matrix swelling and OM rupture, allowing the release of apoptogenic proteins such as cytochrome c, apoptosis-inducing factor, and procaspases [12,13]. Proteins of the bcl-2 family regulate the release of cytochrome c. Antiapoptotic members of the bcl family (Bcl-2 and Bcl-XL) prevent cytochrome c release, whereas the proapoptotic members (Bax and Bak) exert the opposite effect [14]. Bax has been shown to interact with ANT to induce PTP opening and cytochrome c release [15].

Several pharmacological compounds interfere with PTP. For example, cyclosporin A, through its binding to cyclophilin D, prevents PTP opening, and bongkrekic acid and atractyloside are, respectively, a blocker and an inducer of apoptosis via binding to 2 different conformational states of ANT [16]. In addition to modulating pore formation by ANT, Bcl-2 and Bax may modulate the translocase activity of ANT [17]. Although ANT is a pore component, recent studies using mouse liver mitochondria that lack ANT indicate that ANT is non-essential for mitochondrial PTP activity [18]. In contrast, ANT proteoliposomes (but not control liposomes lacking ANT) become permeabilized in response to Ca2+ [10], thiol cross-linker diamide [19], tert-butylhydroperoxide [15], and protein R encoded by human immunodeficiency virus-1 (HIV-1) [20].

ANT1 (but not ANT2) is able to induce apoptosis upon overexpression [21], which may be associated with mitochondrial recruitment of NF-{kappa}B [22]. Vyssokikh et al [23] reported that ANT1 preferentially localizes within the contact sites and associates with cyclophilin D to form mitochondrial PTP [23]. These results demonstrate the specificity of ANT1 in this pathway. Schubert et al [24] found that apoptotic activity of ANT1 may be repressed by cyclophilin D, whereas other workers reported that cyclophilin D can sensitize ANT1 to some apoptotic stimulators, such as Ca2+ and reactive oxygen species (ROS) [25–27].

In cardiac tissue of patients with dilated cardiomyopathy (DCM), ANT1 expression is up-regulated [28]. The cardiomyopathy is characterized by excessive apoptosis [29], and it has been proposed that this apoptosis is mediated by ANT1 [21]. Apoptosis is induced at an early stage of left ventricular hypertrophy (LVH) in response to pressure overload [30], although whether or not ANT1 participates in the regulation of apoptosis during the process is still unknown.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Animals.  Male Sprague–Dawley rats (12 weeks old, body weight 170 to 230 g) were obtained from the Jinling Hospital Experimental Animal Center. The rats were housed in a temperature-controlled room (18–22°C) and were given ad libitum access to food and water. Rats were randomly assigned to 2 groups: (a) treated group (n = 21), and (b) control group (n = 21). All procedures were in accordance with the APS Guiding Principles in the Care and Use of Animals.

Surgical procedures.  For the treated group, surgical procedures were conducted as previously reported [31]. Briefly, rats were anesthetized with sodium pentobarbital (40 mg/kg, ip). After tracheal intubation, the rats were kept under the control of a respirator. Left thoracotomy was performed at the fifth intercostal space to expose the aorta, and a length of surgical silk suture (5–0) was positioned around the midthoracic segment. A needle with outer diameter of 0.45 mm was placed on top of the aortic segment. The aorta and the needle were tied together with the suture. The needle was retrieved immediately, leaving a 0.45 mm lumen diameter at the constriction site. The chest was closed with air suction. The endotracheal tube was removed when the rat awakened. In the control group, the rats were operated upon in the same fashion as the treated group, but without aortic constriction.

Experimental protocol.  At 1, 2, 4, 7, 14, 21, and 30 days post-operation, rats (n= 3 at each time point from the treated and the control groups) were anesthetized with sodium pentobarbital (35 mg/kg, ip) and body weights were measured. Via a catheter introduced in a carotid artery, each rat’s blood pressure was recorded with a physiograph (Sirecust 960, Siemens Co.). The heart was then rapidly excised and rinsed with cold saline (4°C). After both atria and the large vessels had been dissected from the base of the heart, the right ventricular free wall was separated from the remaining portion of the heart, and the left ventricle (including the interventricular septum) was weighed. The ventricular weight was divided by the body weight to estimate left ventricular hypertrophy (LVH index). A sample of left ventricular free wall (100 mg) was rapidly frozen in liquid nitrogen and stored at –80°C until it was processed for RNA extraction. The remainder of the left ventricle was fixed in formalin; tissue slices were embedded in paraffin and 5-µm sections were mounted on slides for apoptosis detection.

RT-PCR assay for ANT1 mRNA.  Each sample (100 mg) of frozen cardiac tissue was pulverized and homogenized, and total RNA was extracted with TripureTM Isolation Reagent (Roche Molecular Biochemicals). RNA samples were tested for purity and concentration by measuring their uv absorption at 260 nm and 280 nm. The ratio A260/A280 was >1.9 for all RNA extracts. Reverse transcription (total RNA, 10 µg) was performed using an oligo(dT)15 primer (Promega) according to the manufacturer’s instructions. Amplification by PCR was carried out with a thermocycler (PE 2400, PerkinElmer), using 10 µl RT products as templates in a 25 µl reaction volume. The amplification conditions were 30 cycles with denaturation (45 sec at 92°C), annealing (50 sec at 58°C), and extension (70 sec at 72°C, with final extension for 7 min at 72°C. To semi-quantify the PCR products, an invariant mRNA of ß-actin was used as an internal control. The primers for PCR referenced the cDNA sequence reported by Gene Bank (GeneBank accession number: 398592, 13592132). ANT1:

sense 5'-TAGGCAATAGCATAAGAGCGGC-3',

antisense 5'-GTCCAGTGGGTAGACGAAGC-3', 459bp;

ß-actin:

sense 5'-TTGTAACCAACTGGGACGATATGG-3',

antisense 5'-GATCTTGATCTTCATGGTGCTAGG-3', 751bp.

The PCR products were separated by electrophoresis on 2% agarose gel and analyzed with an image analyzer (EDAS-290, version 3.5, Eastman Kodak Co.). Relative mRNA levels for ANT1 were estimated as previously reported [32].

Apoptosis assay.  Apoptosis was detected in tissue sections by terminal transferase–mediated dUTP nick end-labeling (TUNEL), using a TUNEL test kit (Boehringer Mannheim) according to the manufacturer’s instructions. For quantification of TUNEL-positive cells, 8 fields per section were examined at 400-fold magnification and analyzed with an image analysis system (HPIAS-1000, Tongji Qianping Image Engineering). The myocardial apoptotic index (MAI) was calculated by the following formula: (number of TUNEL-positive cell nuclei per field / total number of cell nuclei per field), as previously described [33].

Statistics.  Data were expressed as mean ± SD. Differences at each time point (between groups and within groups) were analyzed by one-factor ANOVA with post-hoc comparisons. A value of p <0.05 was considered significant.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Arterial blood pressure (ARP) and left ventricular hypertrophy (LVH).  Fig. 1Go shows that the ABP of treated rats was significantly elevated at 1 day post-surgery (122 ± 5.6 mmHg), compared to control rats (95 ± 2.8 mmHg, p <0.05), and increased steadily thereafter, reaching a maximum at 30 days post-surgery (188 ± 4.1 mmHg vs 102 ± 5.9 mmHg in controls, p <0.05). Fig. 2Go shows that the LVH index became significantly elevated at 4 days post-surgery in the treated rats compared to controls (3.45 ± 0.20 vs 3.06 ± 0.07, p <0.05). The LVH index gradually increased to a maximum at 30 days (4.55 ± 0.32 vs 3.22 ± 0.03 in controls, p <0.05). These findings confirmed that the rat model of pressure overload-induced cardiac hypertrophy was valid.


Figure 1
View larger version (14K):
[in this window]
[in a new window]
  		Fig. 1. Aortic blood pressure (ABP) in rats with thoracic aortic constriction (*p <0.05 vs corresponding controls, d = day post-surgery).

 

Figure 2
View larger version (13K):
[in this window]
[in a new window]
  		Fig. 2. Left ventricular hypertrophy (LVH) in rats with thoracic aortic constriction. The left ventricle weight (including the interventricular septum) was divided by the body weight to obtain the hypertrophy index (*p <0.05 vs corresponding controls, d = day post-surgery).

 
Expression of myocardial mRNA for ANT1.  Fig. 3Go shows that myocardial expression of ANT1 mRNA in the treated group increased significantly at day 4 post-surgery (1.78 ± 0.11 units vs 1.41 ± 0.12 units in controls, p <0.05). The ANT1 mRNA levels in treated rats peaked at 7 days (3.07 ± 0.28 units vs 1.38 ± 0.07 in controls, p <0.05), decreased rapidly to baseline at 14 days post-surgery, and remained at the baseline until the study ended at 30 days post-surgery. No significant fluctuations of expression of myocardial ANT1 mRNA were observed in the controls at any time-point following sham surgery.


Figure 3
View larger version (15K):
[in this window]
[in a new window]
  		Fig. 3. The mRNA levels for ANT1 in myocardium of rats with thoracic aortic constriction (*p <0.05 vs corresponding controls, d = day post-surgery)

 
Apoptosis of cardiomyocytes.  As shown in Fig. 4Go, assays by the TUNEL method revealed that in treated rats, the myocardial apoptosis index (MAI) immediately increased at 1 day post-surgery (0.18 ± 0.03 units) and reached a plateau at 4 days (0.31 ± 0.06) and 7 days (0.30 ± 0.04). The MAI declined at 14 days (0.16 ± 0.05) and reached a low level (0.06 ± 0.03) at 30 days post-surgery. In the control group, apoptosis was undetectable at any interval following sham surgery.


Figure 4
View larger version (14K):
[in this window]
[in a new window]
  		Fig. 4. Myocardial apoptotic index (MAI) in rats with thoracic aortic constriction. Apoptosis was assayed by the TUNEL-labeling method (*p <0.05 vs controls; d = day post-surgery).

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
In the present study, apoptosis of cardiocytes was increased during the early stages of the LVH that developed in response to pressure overload. Condorelli et al [34] also showed that pressure overload caused an increase of cardiocyte apoptosis and contributed to the transition from LVH to heart failure, which may be associated with up-regulation of Bax and reduction of Bcl-2 in cardiomyocytes. Condorelli and coworkers did not assay apoptosis serially, but only at 1 interval (18 weeks). In contrast, we monitored apoptosis serially throughout the present study. Our results confirm the findings of Condorelli et al [34] and are consistent with the hypothesis that apoptosis contributes to the transition from LVH to heart failure. Thus, apoptotic depletion of cardiomyocytes may cause loss of contractile force and gradual progression of systolic dysfunction.

Overstretching of cardiocytes has been reported to induce mitochondrial-dependent apoptosis [35]. The incidence of cardiocyte apoptosis was correlated with the tensile force loaded on isolated myocardial papilli in vitro [36]. Ikeda and colleagues [37] reported that pulmonary arterial banding induced apoptosis and Teiger et al [30] found that acute ascending aortic banding induced cardiocyte apoptosis in vivo. These studies suggest that mechanical factors, including blood pressure, play an important role in cardiocyte apoptosis. Elevated blood pressure may result in overstretch of cardiocytes, which may in turn induce cardiocyte apoptosis. However, in the present study, apoptosis was not correlated directly with blood pressure. Diez et al [38] demonstrated that cardiocyte apoptosis in the left ventricle of SHR is not temporally related to blood pressure. Fortuno et al [39] showed that left ventricular apoptosis is normalized in losartan-treated spontaneously hypertensiverats (SHR) that remained hypertensive. It thus appears that although pressure overload cannot be excluded as a contributing factor in cardiocyte apoptosis, other mechanisms play a more critical role.

In our study, myocardial expression of ANT1 mRNA was up-regulated at 4 days post-surgery, peaked at 7 days, and then decreased to control levels. Together with the cardiocyte apoptosis, this biphasic temporal response is similar to the biphasic pattern reported in apoptosis, resulting in a U or inverted U-shaped dose-response curve [40]. Whether or not the apoptosis is mediated by ANT1 in a dose-dependent manner cannot be answered by our data.

Since ANT1 is activated by overexpression for apoptosis induction, it is interesting to note that this gene is already highly expressed in mitochondria, which suggests that in normal cells it must be kept inactive by other proteins of the PTP, but that the inhibitory effect may be abolished upon over-expression of ANT1 and/or proapoptotic stimuli acting on cells. In fact, it has been demonstrated that cyclophilin D, another component of the PTP, can repress ANT1-induced apoptosis [21,24]. In addition, ANT1 has been shown to be required for apoptosis mediated by Bax [15], and several groups have demonstrated that Bax is up-regulated in cardiocytes due to pressure overload [34,39,41]. These findings suggest that in the present study the role of ANT1 in apoptosis induction could not be excluded even though some evidence of apoptosis was observed prior to increased expression of ANT1 mRNA. The reasons that ANT1 was not up-regulated immediately after operation may include the following: First, it is well known that the balance between energy demand and supply is important for maintaining cardiac function. Second, ANT1 is one of the most abundant proteins located on the mitochondrial IM, and it is also the only known ATP/ADP carrier. In addition, ANT1 has been found to determine the rate of ATP production [42]. Third, the energy demand is determined in part by blood pressure, and in a physiological setting there are always fluctuations of blood pressure. Taken together, this evidence suggests that in the present study, a high expression level of ANT1 may enable it to maintain the energy balance of cardiocytes during the initial stage of pressure overload. ABP increased throughout the experiment; thus, the upregulation of ANT1, just like LVH, may be an adaptive response to the progressively elevated blood pressure.

The most important finding in our study is that ANT1 mRNA expression was up-regulated at 4 days and peaked at 7 days post-surgery, while apoptosis reached a plateau at the same time. Dorner and colleagues [28] demonstrated that the ANT1 is markedly up-regulated in heart tissues from transplant patients with DCM, which are characterized by increased apoptosis in myocytes [29]. It has also been shown that overexpression of ANT1 can induce apoptosis [21]. Taken together, these findings suggest that, in the present study, the apoptosis may be mediated by the up-regulation of ANT1. Our results corroborate the findings of Dorner and colleagues [28] by using a rat model of cardiomyopathy, and we additionally document the temporal development of apoptosis and the expression of ANT1, whereas Dorner et al examined the explanted heart tissues of patients with DCM.

In pressure overload-induced LVH in rabbits, the total mitochondrial volume increased up to 80%, but the mitochondrial volume density decreased as much as 30% with increasing heart size [43]. In our study, crdiocye apoptosis increased during the early stage of pressure overload-induced LVH, which should lead to a decreased number of cardiocytes, but the expression of ANT1 mRNA was not decreased correspondingly. These data suggest that expression of ANT1 mRNA in idividual cardiocytes may be progressively up-regulated during the above process and that hypertrophied cardiocytes may be more prone to apoptosis, as previously proposed [34].

Buzello et al [44] reported that in early LVH of experimental renovascular hypertension in rats, no direct evidence of apoptosis was found, but a relatively higher expression of Bcl-2 was seen 14 days after operation. Ikeda and colleagues [45] demonstrated that the expression of Bcl-XL increased gradually during the progression toward heart failure in Dahl salt-sensitive rats. In the present study, although the ANT1 mRNA expression was increased progressively in single cardiocytes, apoptosis decreased rapidly from a plateau at 14 days to low levels. These findings may reflect up-regulation of protective mechanisms as a consequence of earlier occurring apoptosis, and such mechanisms require further investigation.

Some studies indicate that cytokines might influence the rate of cardiocyte survival and could be an important determinant in cardiocyte apoptosis. For instance, overexpressing serotonin Gq-coupled 5-HT2B receptors in mouse heart induces mitochondrial proliferation associated with hypertrophy, whereas ablation of this receptor leads to mitochondrial structural and functional impairments associated with myofibrillar breakdown and DCM [46]. Other reports have demonstrated a proapoptotic effect of tumor necrosis factor-{alpha} and Fas on cardiocytes in rodents [47–50]. Thus, the roles of these factors in apoptosis during the pressure overload-induced LVH need to be clarified in future studies.

In summary, our results indicate that apoptosis is an important regulatory mechanism involved in the cardiac adaptive response to pressure overload and that it may contribute to the transition from LVH to heart failure. In addition, our data suggest that the apoptosis that occurs in LVH due to pressure overload is mediated, in part, by ANT1.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Gottlieb SS, Dickstein K, Fleck E, Kostis J, Levine TB, LeJemtel T, DeKock M. Hemodynamic and neuro-hormonal effects of the angiotensin II antagonist losartan in patients with congestive heart failure. Circulation 1993;88:1602–1609.[Abstract/Free Full Text]
  2. Hamroff G, Katz SD, Mancini D, Blaufarb I, Bijou R, Patel R, Jondeau G, Olivari MT, Thomas S, Le Jemtel TH. Addition of angiotensin II receptor blockade to maximal angiotensin-converting enzyme inhibition improves exercise capacity in patients with severe congestive heart failure. Circulation 1999;99:990–992.[Abstract/Free Full Text]
  3. Sayegh F, Topouchian J, Hlawaty M, Olzewska M, Asmar R. Regression of left ventricular hypertrophy with moexipril, an angiotensin-converting enzyme inhibitor, in hypertensive patients. Am J Ther 2005;12:3–8.[Medline]
  4. Diez J, Fortuno MA, Ravassa S. Apoptosis in hypertensive heart disease. Curr Opin Cardiol 1998;13:317–325.[Medline]
  5. Newmeyer DD, Farschon DM, Reed JC. Cell-free apoptosis in Xenopus egg extracts: inhibition by Bcl-2 and requirement for an organelle fraction enriched in mitochondria. Cell 1994;79:353–364.[Medline]
  6. Halestrap AP, Brenner C. The adenine nucleotide translocase: a central component of the mitochondrial permeability transition pore and key player in cell death. Curr Med Chem 2003;10:1507–1525.[Medline]
  7. Klingenberg M. Molecular aspects of the adenine nucleotide carrier from mitochondria. Arch Biochem Biophys 1989;270:1–14.[Medline]
  8. Doerner A, Pauschinger M, Badorff A, Noutsias M, Giessen S, Schulze K, Bilger J, Rauch U, Schultheiss HP. Tissue-specific transcription pattern of the adenine nucleotide translocase isoforms in humans. FEBS Lett 1997;414:258–262.[Medline]
  9. Brdiczka D, Beutner G, Ruck A, Dolder M, Wallimann T. The molecular structure of mitochondrial contact sites. Their role in regulation of energy metabolism and permeability transition. Biofactors 1998;8:235–242[Medline]
  10. Ruck A, Dolder M, Wallimann T, Brdiczka D. Reconstituted adenine nucleotide translocase forms a channel for small molecules comparable to the mitochondrial permeability transition pore. FEBS Lett 1998;426:97–101.[Medline]
  11. Halestrap AP, McStay GP, Clarke SJ. The permeability transition pore complex: another view. Biochimie 2002; 84:153–166.[Medline]
  12. Petronilli V, Penzo D, Scorrano L, Bernardi P, Di Lisa F. The mitochondrial permeability transition, release of cytochrome c and cell death. Correlation with the duration of pore openings in situ. J Biol Chem 2001;276: 12030–12034.[Abstract/Free Full Text]
  13. Susin SA, Lorenzo HK, Zamzami N, Marzo I, Snow BE, Brothers GM, Mangion J, Jacotot E, Costantini P, Loeffler M, Larochette N, Goodlett DR, Aebersold R, Siderovski DP, Penninger JM, Kroemer G. Molecular characterization of mitochondrial apoptosis-inducing factor. Nature 1999;397:441–446.[Medline]
  14. Pastorino JG, Chen ST, Tafani M, Snyder JW, Farber JL. The overexpression of Bax produces cell death upon induction of the mitochondrial permeability transition. J Biol Chem 1998;273:7770–7775.[Abstract/Free Full Text]
  15. Marzo I, Brenner C, Zamzami N, Jurgensmeier JM, Susin SA, Vieira HL, Prevost MC, Xie Z, Matsuyama S, Reed JC, Kroemer G. Bax and adenine nucleotide translocator cooperate in the mitochondrial control of apoptosis. Science 1998;281:2027–2031.[Abstract/Free Full Text]
  16. Le Quoc K, Le Quoc D. Involvement of the ADP/ATP carrier in calcium-induced perturbations of the mitochondrial inner membrane permeability: importance of the orientation of the nucleotide binding site. Arch Biochem Biophys 1988;265:249–257.[Medline]
  17. Belzacq AS, Vieira HL, Verrier F, Vandecasteele G, Cohen I, Prevost MC, Larquet E, Pariselli F, Petit PX, Kahn A, Rizzuto R, Brenner C, Kroemer G. Bcl-2 and Bax modulate adenine nucleotide translocase activity. Cancer Res 2003;63:541–546.[Abstract/Free Full Text]
  18. Kokoszka JE, Waymire KG, Levy SE, Sligh JE, Cai J, Jones DP, MacGregor GR, Wallace DC. The ADP/ATP translocator is not essential for the mitochondrial permeability transition pore. Nature 2004;427:461–465.[Medline]
  19. Costantini P, Belzacq AS, Vieira HL, Larochette N, de Pablo MA, Zamzami N, Susin SA, Brenner C, Kroemer G. Oxidation of a critical thiol residue of the adenine nucleotide translocator enforces Bcl-2-independent permeability transition pore opening and apoptosis. Oncogene 2000;19:307–314.[Medline]
  20. Jacotot E, Ravagnan L, Loeffler M, Ferri KF, Vieira HL, Zamzami N, Costantini P, Druillennec S, Hoebeke J, Briand JP, Irinopoulou T, Daugas E, Susin SA, Cointe D, Xie ZH, Reed JC, Roques BP, Kroemer G. The HIV-1 viral protein R induces apoptosis via a direct effect on the mitochondrial permeability transition pore. J Exp Med 2000;191:33–46.[Abstract/Free Full Text]
  21. Bauer MK, Schubert A, Rocks O, Grimm S. Adenine nucleotide translocase-1, a component of the permeability transition pore, can dominantly induce apoptosis. J Cell Biol 1999;147:1493–1502.[Abstract/Free Full Text]
  22. Zamora M, Merono C, Vinas O, Mampel T. Recruitment of NF-kappaB into mitochondria is involved in adenine nucleotide translocase 1 (ANT1)-induced apoptosis. J Biol Chem 2004;279:38415–38423.[Abstract/Free Full Text]
  23. Vyssokikh MY, Katz A, Rueck A, Wuensch C, Dorner A, Zorov DB, Brdiczka D. Adenine nucleotide translocator isoforms 1 and 2 are differently distributed in the mitochondrial inner membrane and have distinct affinities to cyclophilin D. Biochem J 2001;358:349–358.[Medline]
  24. Schubert A, Grimm S. Cyclophilin D, a component of the permeability transition-pore, is an apoptosis repressor. Cancer Res 2004;64:85–93.[Abstract/Free Full Text]
  25. Connern CP, Halestrap AP. Recruitment of mitochondrial cyclophilin to the mitochondrial inner membrane under conditions of oxidative stress that enhance the opening of a calcium-sensitive non-specific channel. Biochem J 1994;302:321–324.
  26. Connern CP, Halestrap AP. Chaotropic agents and increased matrix volume enhance binding of mitochondrial cyclophilin to the inner mitochondrial membrane and sensitize the mitochondrial permeability transition to [Ca2+]. Biochemistry 1996;35:8172–8180.[Medline]
  27. Li Y, Johnson N, Capano M, Edwards M, Crompton M. Cyclophilin-D promotes the mitochondrial permeability transition but has opposite effects on apoptosis and necrosis. Biochem J 2004;383:101–109.[Medline]
  28. Dorner A, Schultheiss HP. The myocardial expression of the adenine nucleotide translocator isoforms is specifically altered in dilated cardiomyopathy. Herz 2000;25:176–180.[Medline]
  29. Narula J, Kolodgie FD, Virmani R. Apoptosis and cardiomyopathy. Curr Opin Cardiol 2000;15:183–188.[Medline]
  30. Teiger E, Than VD, Richard L, Wisnewsky C, Tea BS, Gaboury L, Tremblay J, Schwartz K, Hamet P. Apoptosis in pressure overload-induced heart hypertrophy in the rat. J Clin Invest 1996;97:2891–2897.[Medline]
  31. Xu C, Lee S, Singh TM, Sho E, Li X, Sho M, Masuda H, Zarins CK. Molecular mechanisms of aortic wall remodeling in response to hypertension. J Vasc Surg 2001;33:570–578.[Medline]
  32. Marone M, Mozzetti S, De Ritis D, Pierelli L, Scambia G. Semiquantitative RT-PCR analysis to assess the expression levels of multiple transcripts from the same sample. Biol Proc Online 2001;3:19–25.
  33. Bonderman D, Gharehbaghi-Schnell E, Wollenek G, Maurer G, Baumgartner H, Lang IM. Mechanisms underlying aortic dilatation in congenital aortic valve malformation. Circulation 1999;99:2138–2143.[Abstract/Free Full Text]
  34. Condorelli G, Morisco C, Stassi G, Notte A, Farina F, Sgaramella G, de Rienzo A, Roncarati R, Trimarco B, Lembo G. Increased cardiomyocyte apoptosis and changes in proapoptotic and antiapoptotic genes bax and bcl-2 during left ventricular adaptations to chronic pressure overload in the rat. Circulation 1999;99:3071–3078.[Abstract/Free Full Text]
  35. Liao XD, Wang XH, Jin HJ, Chen LY, Chen Q. Mechanical stretch induces mitochondria-dependent apoptosis in neonatal rat cardiomyocytes and G2/M accumulation in cardiac fibroblasts. Cell Res 2004;14:16–26.[Medline]
  36. Cheng W, Li B, Kajstura J, Li P, Wolin MS, Sonnenblick EH, Hintze TH, Olivetti G, Anversa P. Stretch-induced programmed myocyte cell death. J Clin Invest 1995;96: 2247–2259.[Medline]
  37. Ikeda S, Hamada M, Hiwada K. Cardiomyocyte apoptosis with enhanced expression of P53 and Bax in right ventricle after pulmonary arterial banding. Life Sci 1999;65:925–933.[Medline]
  38. Diez J, Panizo A, Hernandez M, Vega F, Sola I, Fortuno MA, Pardo J. Cardiomyocyte apoptosis and cardiac angiotensin-converting enzyme in spontaneously hypertensive rats. Hypertension 1997;30:1029–1034.[Abstract/Free Full Text]
  39. Fortuno MA, Ravassa S, Etayo JC, Diez J. Overexpression of Bax protein and enhanced apoptosis in the left ventricle of spontaneously hypertensive rats: effects of ANT1 blockade with losartan. Hypertension 1998;32: 280–286.[Abstract/Free Full Text]
  40. Calabrese EJ, Baldwin LA. The frequency of U-shaped dose responses in the toxicological literature. Toxicol Sci 2001;62:330–338.[Abstract/Free Full Text]
  41. Moorjani N, Catarino P, El-Sayed R, Al-Ahmed S, Meyer B, Al-Mohanna F, Westaby S. A pressure overload model to track the molecular biology of heart failure. Eur J Cardiothorac Surg 2003;24:920–925.[Abstract/Free Full Text]
  42. Atlante A, Seccia TM, Pierro P, Vulpis V, Marra E, Pirrelli A, Passarella S. ATP synthesis and export in heart left ventricle mitochondria from spontaneously hypertensive rat. Int J Mol Med 1998;1:709–716.[Medline]
  43. Kayar SR, Weiss HR. Diffusion distances, total capillary length and mitochondrial volume in pressure-overload myocardial hypertrophy. J Mol Cell Cardiol 1992;24: 1155–1166.[Medline]
  44. Buzello M, Boehm C, Orth S, Fischer B, Ehmke H, Ritz E, Mall G, Amann K. Myocyte loss in early left ventricular hypertrophy of experimental renovascular hypertension. Virchows Arch 2003;442:364–371.[Medline]
  45. Ikeda S, Hamada M, Qu P, Hiasa G, Hashida H, Shigematsu Y, Hiwada K. Relationship between cardiomyocyte cell death and cardiac function during hypertensive cardiac remodelling in Dahl rats. Clin Sci 2002; 102:329–335.[Medline]
  46. Nebigil CG, Maroteaux L. Functional consequence of serotonin/5-HT2B receptor signaling in heart: role of mitochondria in transition between hypertrophy and heart failure? Circulation 2003;108:902–908.[Free Full Text]
  47. Kubota T, McTiernan CF, Frye CS, Slawson SE, Lemster BH, Koretsky AP, Demetris AJ, Feldman AM. Dilated cardiomyopathy in transgenic mice with cardiac-specific overexpression of tumor necrosis factor-{alpha}. Circ Res 1997;81:627–635.[Abstract/Free Full Text]
  48. Bozkurt B, Kribbs SB, Clubb FJ Jr, Michael LH, Didenko VV, Hornsby PJ, Seta Y, Oral H, Spinale FG, Mann DL. Pathophysiologically relevant concentrations of tumor necrosis factor-{alpha} promote progressive left ventricular dysfunction and remodeling in rats. Circulation 1998;97:1382–1391.[Abstract/Free Full Text]
  49. Philipp S, Pagel I, Hohnel K, Lutz J, Buttgereit J, Langenickel T, Hamet P, Dietz R, Willenbrock R. Regulation of caspase 3 and Fas in pressure overload-induced left ventricular dysfunction. Eur J Heart Fail 2004;6:845–851.[Abstract/Free Full Text]
  50. Fu YC, Chi CS, Yin SC, Hwang B, Chiu YT, Hsu SL. Norepinephrine induces apoptosis in neonatal rat cardiomyocytes through a reactive oxygen species-TNF alpha-caspase signaling pathway. Cardiovasc Res 2004;62:558–567.[Abstract/Free Full Text]




This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Hang, T.
Right arrow Articles by Ren, H.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Hang, T.
Right arrow Articles by Ren, H.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS