© 2001 by European Society of Cardiology
Copyright © 2000, European Society of Cardiology
Accumulation of molecules involved in 
1-adrenergic signal within caveolae: caveolin expression and the development of cardiac hypertrophy
aDepartment of Medicine and Physiology, Yokohama City University School of Medicine, Yokohama 236, Japan
bCardiovascular Research Institute, Department of Medicine, University of Medicine and Dentistry of New Jersey, Newark, NJ 07103, USA
* Corresponding author. Tel.: +81-45-787-2633; fax: +81-45-787-2637 umemuras{at}med.yokohama-cu.ac.jp
Received 20 November 2000; accepted 10 May 2001
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Abstract |
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 Top Abstract 1 Introduction2 Methods3 Results4 DiscussionReferences |
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Objective: Caveolin, a major protein component of caveolae, is now considered to be an inhibitor of cellular growth and proliferation. In this study, we examined the localization of the molecules involved in
1-adrenergic receptor signal relative to that of caveolin in the heart and the changes in caveolin expression during the development of hypertrophy in SHR. Methods: We purified the caveolar protein fractions from rat cardiac tissues, H9C2 cells, and rat vascular smooth muscle cells. Using radioligand receptor binding assay and immunoblot analysis, we examined the distribution and the amount of 1-AR and caveolin. Results: Caveolin-3, the 1-adrenergic receptor, Gq and PLC-β ubtypes (PLC-β1, -β3) were found exclusively in the caveolar fraction in the above tissues. Caveolin-3 were co-immunoprecipitated with 1-adrenergic receptor and Gq from the cardiac tissues. The amount of caveolin subtypes expression (caveolin-1 and -3) and the amount of the 1-adrenergic receptor were examined in the hearts of SHR and age-matched WKY (4- and 24-weeks-old). The amount of caveolin-3 expression was significantly smaller in SHR at 24-weeks-old than that in SHR at 4-weeks-old and that in WKY at 24-weeks-old. Conclusions: The molecules involved in 1-adrenergic signaling are confined to the same microdomain as caveolin. A decrease in caveolin-3 expression may play a role in the development of cardiac hypertrophy in SHR, presumably through de-regulating the inhibition of growth signal in the hearts of SHR in the hypertrophic stage.
KEYWORDS Diabetes; Hypertrophy; Receptors; Signal transduction; Smooth muscle
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1 Introduction |
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TopAbstract1 Introduction2 Methods3 Results4 DiscussionReferences |
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Caveolae are flask shaped, 50–100 nm invaginations of the plasma membrane characterized by high contents of cholesterol and glycosphingolipids [1]. Caveolin, an approximately 20-kDa integral membrane protein, is a principal component of the caveolae. The role of caveolin in compartmentation and modulation of a number of plasma membrane-linked signal transduction pathways is rapidly being established. Importantly, caveolin is now known as an inhibitor of cellular growth and proliferation. Caveolin directly interacts with many growth factor receptors including those for EGF, PDGF and VEGF, leading to the inhibition of their function [2–4]. In rapidly dividing cells, such as subconfluent cells and tumor cells, the downregulation of caveolin protein expression has been reported [5]. Furthermore, the re-expression of caveolin in human breast cancer cells resulted in substantial growth inhibition [6].
Catecholamines also play pivotal roles in cellular growth. Persistent stimulation of cardiac cells by catecholamine, for example, has been known as a prime example of catecholamine-induced cardiac hypertrophy [7]. Stimulation of vascular smooth muscle cells with catecholamine leads to the proliferation of vascular smooth muscle cells. We and other have demonstrated that the molecules involved in the catecholamine signal, such as the β-adrenergic receptor, G proteins, adenylate cyclase, and protein kinase A, are accumulated in caveolae. The direct regulation of G proteins, adenylate cyclase and protein kinase A by caveolin has also been demonstrated [8–11].
Despite the above findings, the relationship between caveolin and the molecules involved in 1-adrenergic receptor (AR) signal has not been elucidated. 1-AR signal is known to play a major role in the development of cardiac hypertrophy and growth of vascular smooth muscle cells as has been demonstrated in many animal models including Spontaneously Hypertensive Rats (SHR) [12–15]. In this study, we examined the localization of the molecules involved in 1-AR signal relative to that of caveolin in the heart and the changes in caveolin expression during the development of hypertrophy in SHR.
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2 Methods |
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TopAbstract1 Introduction2 Methods3 Results4 DiscussionReferences |
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2.1 Materials
Dulbecco's modification of Eagle's medium (DMEM), fetal calf serum (FCS), penicillin, and streptomycin were obtained from GIBCO BRL (Rockville, MD). Anti-caveolin-3 monoclonal antibody was obtained from Transduction Laboratories (Lexington, KY). Anti-Gq, Gs, PLCβ1, PLCβ3, PLC
2 polyclonal antibodies were obtained from Santa Cruz Biotechnology Inc. (Santa Cruz, California). Anti 1-AR polyclonal antibody was obtained from Calbiochem-Novabiochem (La Jolla, California). Horseradish peroxidase-linked goat anti-rabbit and goat anti-mouse IgG, protein G-agarose were purchased from Amersham Pharmacia Biotech (Buckinghamshire, UK). [3H]prazosin for radioligand binding assays was purchased from NEN Life Science Products, Inc. (Boston, MA). Most other reagents were purchased from Sigma (St. Louis, MO).
2.2 Cell culture
VSMCs were aseptically isolated from thoracic aortic explants of 5-week-old Sprague–Dawley rats [16]. Cells were cultured in DMEM supplemented with 10% calf serum, penicillin, streptomycin and equilibrated with 95% air and 5% CO2. H9C2 cells were cultured in DMEM supplemented with 10% calf serum, penicillin, streptomycin and equilibrated with 95% air and 5% CO2.
2.3 Animals
Sprague–Dawley rats were purchased from Japan SLC. Inc. (Tokyo, Japan). Wister Kyoto (WKY) rats and SHR were purchased from Charles River Breeding Laboratories (Sagamihara, Japan). WKY aged 6-weeks-old were used in the study of subcellular distribution of signaling molecules and immunoprecipitation. Male SHR and WKY aged 4- and 24-weeks-old were used in the rest of the study. All rats were decapitated and the hearts were rapidly excised, washed in cold saline, and divided into ventricle and atrium. The ventricles were frozen in liquid nitrogen and stored at –80°C until assay.
These animals were maintained and used for the experiments at Yokohama City University School of Medicine Laboratory Animal Facility. The experiments were done under the guidelines for animal experiments set by the Animal Experiment Committee of Yokohama City University School of Medicine.
2.4 Radioligand receptor binding assay
The membrane preparations of rat ventricular myocardium and the 1-AR binding assay were performed by a previously described method [17] with some modifications. The left ventricle was cut from a stored heart, homogenized in an ice-cold Buffer A (200 mM sucrose, 50 mM Tris/HCl (pH 8.0), 1 mM EGTA, 1 mM EDTA, 1 mM dithiothreitol, 10 µg/ml leupeptin, 0.1 mM phenylmetheylsulfonyl fluoride, 50 U/ml egg white trypsin inhibitor, and 2 µg/ml aprotinin) using a Brinkman Polytron (Kinematica Littau) with two 10-s bursts at a setting of 10. The homogenate was centrifuged at 300 g for 10 min at 4°C to eliminate tissue debris. The supernatant was further centrifuged at 100 000 g for 40 min at 4°C. The final pellet was resuspended in the same buffer without EGTA. The crude membrane preparations were stored at –80°C until use.
For the determination of 1-AR, membrane fractions were incubated for 30 min at 25°C with [3H]prazosin (1.0 nM, final concentration) in a total volume of 150 µl. Non-specific binding was determined in the presence of 100 µM prazosin. Assays were performed in duplicates and the incubation was terminated by rapid filtration through Whatman GF/C filters. Under this condition, the binding of [3H]prazosin to cardiac membrane preparations was in a linear range at least for 30 min. In our typical binding assays, the specific binding was approximately 15% of the total binding. The filters were washed three times with 5 ml cold Tris–Mg–ascorbic acid buffer and dried, followed by counting in vials containing 6 ml of scintillant. The radioactivity was determined in a liquid scintillation counter (LS 5801, Beckman Instruments Inc., Fullerton, CA).
2.5 Cell fractionation
Caveolin-enriched membrane fractions were prepared using the method of Li et al. with minor modifications [18]. Briefly, cardiac tissues or cells were homogenated in 2 ml of 500 mM sodium carbonate (pH 11.0) with protease inhibitors (1 µg/ml leupeptin, 0.1 mM phenylmetheylsulfonyl fluoride (PMSF), 50 U/ml egg white trypsin inhibitor) and lysed by sonication (three 10-s bursts with minimal output power) using a Branson sonicator 250 (Branson Ultrasonic Corp.). The lysate was then adjusted to 45% sucrose by mixing with 2 ml of 90% sucrose prepared in MBS (25 mM Mes, pH 6.5, 0.15 mM NaCl) and placed at the bottom of 5 and 35% discontinuous sucrose gradient (in MBS containing 100 mM sodium carbonate) for an overnight ultra-centrifugation (260 000 g). Fractions were removed sequentially from the top and designated as fractions 1 through 13. Caveolin-enriched, caveolar fractions are contained in light vesicle fractions [18], which were fractions 5 and 6 in our study. Protein concentration in each fraction was quantified by Lowry assay. When receptor binding assays were performed, each fraction was neutralized by adding HCl.We typically found 5% of the total cell protein accumulated in caveolar fractions (fractions 5 and 6).
2.6 Immunoprecipitation
Rat cardiac tissues were homogenized in Buffer B (20 mM HEPES (pH 7.5), 150 mM NaCl, 1 mM EDTA, 10 µg/ml leupeptin, 0.1 mM PMSF, 1.0% Triton X-100). Immunoprecipitation was performed as previously described [3] using protein G-agarose and anti-1-AR or anti-Gq polyclonal antibody. After washing three times with Buffer B, the bound proteins were solubilized in Buffer C (0.125 M Tris–HCl (pH 6.8), 2% SDS, 10% glycerol) followed by the detection of caveolin-3 by immunoblotting.
2.7 Immunoblot analysis
Aliquots from each fraction of the sucrose centrifuge fractionation were separated by SDS–polyacrylamide gel electrophoresis (SDS–PAGE). Proteins were transferred to PVDF membranes. Non-specific binding was blocked by the incubation for 1 h with 5% skim milk, 5% BSA in phosphate buffered saline containing 0.1% Tween 20. Immunoblot analysis was carried out with each specific antibody (anti-caveolin-3 monoclonal antibody and anti-caveolin-1, Gq, Gs, PLCβ1, PLCβ3, PLC2 polyclonal antibodies). The blots were then washed extensively and incubated with horseradish peroxidase-linked goat anti-rabbit or goat anti-mouse IgG. Bands were visualized by the Western blotting detection system from PIERCE (Rockford, IL).
2.8 Data analysis and statistics
All data were expressed as means±S.E.M. ANOVA with subsequent Scheffe's test was used to determine the significance in multiple comparisons. A value of P<0.05 was considered statistically significant.
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3 Results |
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TopAbstract1 Introduction2 Methods3 Results4 DiscussionReferences |
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3.1 Molecules involved in
1-AR signal are accumulated in caveolin-enriched fractionSodium carbonate-based detergent-free cell lysates were prepared from rat cardiac tissues. Lysates were fractionated on a discontinuous sucrose density gradient. The protein content of each fraction was determined according to a modified Lowry procedure. As shown in Fig. 1A, most cellular protein was found in fractions 9 to 13 while approximately 5% of the total cellular protein was in fraction 5 and 6 which was similar to the findings in our previous studies [19,20]. Caveolae and their major structural component, caveolin, have been shown to be enriched in these light vesicle fractions, i.e., fractions 5 and 6.
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We then examined the distribution of
1-AR and caveolin among these fractions. Aliquots taken from each of the sucrose density gradient fractions were subjected to radioligand binding assays and immunoblotting. Caveolin-3, a myocyte-specific caveolin subtype, was detected exclusively in fractions 5 and 6 (Fig. 1C). In the same fractions, we detected 1-AR (Fig. 1B). Interestingly Gq, PLC-β-1, and -3, which are coupled to 1-AR, were also found in these fractions. In contrast, PLC-, a PLC subtype not coupled to 1-adrenergic signaling, was found in non-caveolar fractions (fractions 9–13, Fig. 1C). These finding suggested that 1-AR and its related molecules (Gq and PLC-β subtypes, but not PLC-subtype) are accumulated in the same fraction as caveolin.
We also examined whether 1-AR was accumulated with caveolin in other cell types. As shown in Fig. 2, 1-AR was detected in the same fractions as caveolin-3 in vascular smooth muscle cells and H9C2 cells (a rat cardiac myoblast cell line), suggesting that 1-AR is colocalized with caveolin-3 in many cell types.
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3.2
1-AR and Gq are physically bound to caveolin in cardiac tissuesThe above findings do not necessarily indicate that caveolin and
1-AR are physically bound within caveolae. To examine the interaction of caveolin with 1-AR, we performed immunoprecipitation assays. Cardiac tissue homogenates were subjected to immunoprecipitation by antibodies raised against 1-AR or Gq, followed by the immunodetection by an anti-caveolin-3 antibody. As shown in Fig. 3, caveolin-3 was immunoprecipitated by an 1-AR antibody or a Gq-antibody while not by anti-mouse IgG (Fig. 3), indicating the interaction between caveolin and 1-AR as well as Gq. However, co-immunoprecipitation of PLC with caveolin was difficult, presumably due to poor affinity of the antibody used, or due to indirect interaction between PLC and caveolin.
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3.3 Expression of
1-AR and caveolin in the hearts of WKY and SHRIt is well known that
1-AR signal plays a key role in the development of cardiac hypertrophy [21,22]. It is also well known that caveolin inhibits growth factor signaling and G protein coupled receptor signaling [23]. Thus, we examined whether the expression of 1-AR and caveolin was changed during the development of cardiac hypertrophy in SHR (4- and 24-weeks-old). We used the hearts from WKY as control.
The amount of 1-AR expression was greater in SHR than in WKY regardless of their age (by 28.4±2.5% at 4 weeks and 26.6±2.3% at 24 weeks, n=4, P<0.05) (Fig. 4) while the expression of 1-AR was decreased in older rats than in younger rats in both SHR and WKY, suggesting that 1-AR expression is increased in SHR, but that ontogenic changes were similar in both rat strains. Caveolin-3 expression showed an increase with age in WKY while decreased significantly with age in SHR (by 23.7±4.2%, n=4, P<0.05) (Fig. 5A), suggesting that ontogenic changes of caveolin-3 expression were different between SHR and WKY. In contrast, caveolin-1 expression was similar between different age groups of the same rat strain and between SHR and WKY at any ages (Fig. 5B). Thus, caveolin-3, but not caveolin-1 expression, was altered in SHR from WKY.
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4 Discussion |
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TopAbstract1 Introduction2 Methods3 Results4 DiscussionReferences |
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In this study, we have demonstrated that the molecules involved in
1-AR signal (1-AR, Gq protein, and PLC-β subtypes) are accumulated in the same subcellular fraction with caveolin in rat cardiac tissues. In particular, 1-AR and Gq were bound to caveolin as demonstrated by our immunoprecipitation study. Similar colocalization of 1-AR with caveolin was demonstrated in other cell types such as H9C2 cells (rat cardiac myoblasts) and rat vascular smooth muscle cells, which are contained in cardiac tissues. Thus, 1-AR and caveolin may reside within the same microdomain of the plasma membrane in many cell types in the heart.
The rapid amplification of 1-AR signaling involves the sequential activation of multiple signaling molecules ranging from the receptor to PLC, leading to the increased production of IP3 and calcium signaling. The common view of the 1 agonist-induced interaction between signaling molecules is based on random collisions between proteins that diffuse freely in the plasma membrane. Our study, however, has suggested the non-random distribution of 1-AR in the plasma membrane and that caveolae may act as a microdomain within the plasma membrane to accumulate the molecules involved in -adrenergic signaling, leading to the facilitation of the interaction between these molecules within the plasma membrane.
We have also demonstrated that the expression of 1-AR was increased in SHR relative to that in WKY in both non-hypertrophic (4-week) and hypertrophic (24-week) stages. Since 1-AR signal is known to stimulate cardiac hypertrophy [21,22], the increased expression of 1-AR may play a role in the accelerated development of cardiac hypertrophy in SHR. We have also found that the caveolin-3 expression decreased in the hypertrophic stage of SHR, but remained similar throughout aging in WKY. It has been demonstrated that caveolin binds to many growth factor receptors and its downstream molecules such as ras, leading to the inhibition of cellular growth. Thus, it is tempting to speculate that the decreased inhibition, i.e., de-inhibition, of growth factor signal, including 1-AR signal, by caveolin may play a role in facilitating the development of cardiac hypertrophy in SHR. Increased fibrosis and cardiac myocyte loss may be another mechanism to explain the decreased caveolin-3 expression in SHR. However, caveolin-1 expression, which is abundant in fibroblasts, was not increased in the hypertrophic stage of SHR.
The exact molecular mechanism to regulate the caveolin expression remains unknown, however, there have been several mechanisms proposed in previous studies. We have demonstrated that chronic isoproterenol infusion in mice decreased the expression of cardiac caveolin-3 [24]. Treatment of H9C2 cells with forskolin similarly decreased the expression of caveolin-1 and -3, but not caveolin-2 [25]. In this regard, sympathetic nervous activity may be increased in SHR as demonstrated by an increase in myocardial norepinephrine contents and a decreased number of total β-AR in SHR in comparison to WKY [26,27]. Putting together, increased sympathetic nervous activity may play a role in down-regulating caveolin-3 expression in SHR. In addition, Feron et al. have demonstrated that hypercholesterolemia up-regulates caveolin expression [28]; it is interesting to note that plasma cholesterol concentration is lower in SHR than in WKY [29].
The nature of our findings is to suggest that the interaction of molecules involved in 1-adrenergic signaling appears to be more highly organized by caveolae and the caveolin expression may play a role under various pathophysiological conditions such as cardiac hypertrophy.
Time for primary review 23 days.
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Acknowledgements |
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This study was supported by grants from the United States Public Health Service (HL38070 and HL54895), Uehara Memorial Foundation, Japanese Ministry of Education, Welfied Research Foundation, and Kitsuen Kagaku Research Foundation. YI is a recipient of Established Investigator Award of the American Heart Association.
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References |
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TopAbstract1 Introduction2 Methods3 Results4 DiscussionReferences |
|---|
- Sargiacomo M., Sudol M., Tang Z., Lisanti M.P. Signal transducing molecules and glycosyl-phosphatidylinositol-linked proteins form a caveolin-rich insoluble complex in MDCK cells. J Cell Biol (1993) 122:789–807.
[Abstract/Free Full Text] - Couet J., Sargiacomo M., Lisanti M.P. Interaction of a receptor tyrosine kinase, EGF-R, with caveolins. Caveolin binding negatively regulates tyrosine and serine/threonine kinase activities. J Biol Chem (1997) 272:30429–30438.
[Abstract/Free Full Text] - Yamamoto M., Toya Y., Jensen R.A., Ishikawa Y. Caveolin is an inhibitor of platelet-derived growth factor receptor signaling. Exp Cell Res (1999) 247:380–388.[CrossRef][Web of Science][Medline]
- Liu J., Razani B., Tang S., Terman B.I., Ware J.A., Lisanti M.P. Angiogenesis activators and inhibitors differentially regulate caveolin-1 expression and caveolae formation in vascular endothelial cells. Angiogenesis inhibitors block vascular endothelial growth factor-induced down-regulation of caveolin-1. J Biol Chem (1999) 274:15781–15785.
[Abstract/Free Full Text] - Galbiati F., Volonte D., Engelman J.A., Watanabe G., Burk R., Pestell R.G., Lisanti M.P. Targeted downregulation of caveolin-1 is sufficient to drive cell transformation and hyperactivate the p42/44 MAP kinase cascade. EMBO J (1998) 17:6633–6648.[CrossRef][Web of Science][Medline]
- Lee S.W., Reimer C.L., Oh P., Campbell D.B., Schnitzer J.E. Tumor cell growth inhibition by caveolin re-expression in human breast cancer cells. Oncogene (1998) 16:1391–1397.[CrossRef][Web of Science][Medline]
- Ishikawa Y., Homcy C.J. The adenylyl cyclases as integrators of transmembrane signal transduction. Circ Res (1997) 80:297–304.
[Free Full Text] - Schwencke C., Yamamoto M., Okumura S., Toya Y., Kim S.J., Ishikawa Y. Compartmentation of cyclic adenosine 3',5'-monophosphate signaling in caveolae. Mol Endocrinol (1999) 13:1061–1070.
[Abstract/Free Full Text] - Li S., Okamoto T., Chun M., Sargiacomo M., Casanova J.E., Hansen S.H., Nishimoto I., Lisanti M.P. Evidence for a regulated interaction between heterotrimeric G proteins and caveolin. J Biol Chem (1995) 270:15693–15701.
[Abstract/Free Full Text] - Toya Y., Schwencke C., Couet J., Lisanti M.P., Ishikawa Y. Inhibition of adenylyl cyclase by caveolin peptides. Endocrinology (1998) 139:2025–2031.
[Abstract/Free Full Text] - Razani B., Rubin C.S., Lisanti M.P. Regulation of cAMP-mediated signal transduction via interaction of caveolins with the catalytic subunit of protein kinase A. J Biol Chem (1999) 274:26353–26360.
[Abstract/Free Full Text] - Knowlton K.U., Michel M.C., Itani M., Shubeita H.E., Ishihara K., Brown J.H., Chien K.R. The alpha 1A-adrenergic receptor subtype mediates biochemical, molecular, and morphologic features of cultured myocardial cell hypertrophy. J Biol Chem (1993) 268:15374–15380.
[Abstract/Free Full Text] - LaMorte V.J., Thorburn J., Absher D., Spiegel A., Brown J.H., Chien K.R., Feramisco J.R., Knowlton K.U. Gq- and ras-dependent pathways mediate hypertrophy of neonatal rat ventricular myocytes following alpha 1-adrenergic stimulation. J Biol Chem (1994) 269:13490–13496.
[Abstract/Free Full Text] - Chen L., Xin X., Eckhart A.D., Yang N., Faber J.E. Regulation of vascular smooth muscle growth by alpha 1-adrenoreceptor subtypes in vitro and in situ. J Biol Chem (1995) 270:30980–30988.
[Abstract/Free Full Text] - Imai C., Tozawa M., Sunagawa O., Muratani H., Takishita S., Fukiyama K. Alterations of alpha 1-adrenergic receptor densities in right and left ventricles of spontaneously hypertensive rats. Biol Pharm Bull (1995) 18:1001–1005.[Web of Science][Medline]
- Tamura K., Nyui N., Tamura N., Fujita T., Kihara M., Toya Y., Takasaki I., Takagi N., Ishii M., Oda K., Horiuchi M., Umemura S. Mechanism of angiotensin II-mediated regulation of fibronectin gene in rat vascular smooth muscle cells. J Biol Chem (1998) 273:26487–26496.
[Abstract/Free Full Text] - McCaughran J.A. Jr., Juno C.J., O'Malley E. Differential ontogeny of alpha 1-adrenergic and cholinergic receptor sites in the atria and ventricles of the inbred Dahl hypertension-sensitive (S/JR) and -resistant (R/JR) rat. J Auton Nerv Syst (1987) 20:207–220.[CrossRef][Web of Science][Medline]
- Li S., Okamoto T., Chun M., Sargiacomo M., Casanova J.E., Hansen S.H., Nishimoto I., Lisanti M.P. Evidence for a regulated interaction between heterotrimeric G proteins and caveolin. J Biol Chem (1995) 270:15693–15701.
[Abstract/Free Full Text] - Yamamoto M., Toya Y., Schwencke C., Lisanti M.P., Myers M.G. Jr., Ishikawa Y. Caveolin is an activator of insulin receptor signaling. J Biol Chem (1998) 273:26962–26968.
[Abstract/Free Full Text] - Schwencke C., Yamamoto M., Okumura S., Geng Y.-J., Ishikawa Y. Colocalization of β-adrenergic receptors and caveolin within the plasma membrane. J Cell Biochem (1999) 75:64–72.[CrossRef][Web of Science][Medline]
- Zimmer H. Catecholamine-induced cardiac hypertrophy: significance of proto-oncogene expression. J Mol Med (1997) 75:849–859.[CrossRef][Web of Science][Medline]
- Beinlich C.J., Morgan H.E. Control of growth in neonatal pig hearts. Mol Cell Biochem (1993) 119:3–9.[CrossRef][Web of Science][Medline]
- Schlegel A., Volonte D., Engelman J.A., Galbiati F., Mehta P., Zhang X.L., Scherer P.E., Lisanti M.P. Crowded little caves: structure and function of caveolae. Cell Signal (1998) 10:457–463.[CrossRef][Web of Science][Medline]
- Oka N., Asai K., Kudej R.K., Edwards J.G., Toya Y., Schwencke C., Vatner D.E., Vatner S.F., Ishikawa Y. Downregulation of caveolin by chronic beta-adrenergic receptor stimulation in mice. Am J Physiol (1997) 273:C1957–1962.[Web of Science][Medline]
- Yamamoto M., Okumura S., Oka N., Schwencke C., Ishikawa Y. Downregulation of caveolin expression by cAMP signal. Life Sci (1999) 64:1349–1357.[CrossRef][Web of Science][Medline]
- Bohm M., Castellano M., Paul M., Erdmann E. Cardiac norepinephrine, beta-adrenoceptors, and Gi alpha-proteins in prehypertensive and hypertensive spontaneously hypertensive rats. J Cardiovasc Pharmacol (1994) 23:980–987.[Web of Science][Medline]
- Adams M.A., Bobik A., Korner P.I. Differential development of vascular and cardiac hypertrophy in genetic hypertension. Relation to sympathetic function. Hypertension (1989) 14:191–202.
[Abstract/Free Full Text] - Feron O., Dessy C., Moniotte S., Desager J.P., Balligand J.L. Hypercholesterolemia decreases nitric oxide production by promoting the interaction of caveolin and endothelial nitric oxide synthase. J Clin Invest (1999) 103:897–905.[Web of Science][Medline]
- Kitts D.D., Yuan Y.V., Godin D.V. Plasma and lipoprotein lipid composition and hepatic antioxidant status in spontaneously hypertensive (SHR) and normotensive (WKY) rats. Can J Physiol Pharmacol (1998) 76:202–209.[CrossRef][Web of Science][Medline]
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A. A. Lanzafame, L. Turnbull, F. Amiramahdi, J. F. Arthur, H. Huynh, and E. A. Woodcock Inositol phospholipids localized to caveolae in rat heart are regulated by {alpha}1-adrenergic receptors and by ischemia-reperfusion Am J Physiol Heart Circ Physiol, May 1, 2006; 290(5): H2059 - H2065. [Abstract] [Full Text] [PDF]
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 S. Calaghan and E. White Caveolae modulate excitation-contraction coupling and {beta}2-adrenergic signalling in adult rat ventricular myocytes Cardiovasc Res, March 1, 2006; 69(4): 816 - 824. [Abstract] [Full Text] [PDF]
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B. P. Head, H. H. Patel, D. M. Roth, N. C. Lai, I. R. Niesman, M. G. Farquhar, and P. A. Insel G-protein-coupled Receptor Signaling Components Localize in Both Sarcolemmal and Intracellular Caveolin-3-associated Microdomains in Adult Cardiac Myocytes J. Biol. Chem., September 2, 2005; 280(35): 31036 - 31044. [Abstract] [Full Text] [PDF]
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 Y. G Wang, E. N Dedkova, X Ji, L. A Blatter, and S. L Lipsius Phenylephrine acts via IP3-dependent intracellular NO release to stimulate L-type Ca2+ current in cat atrial myocytes J. Physiol., August 15, 2005; 567(1): 143 - 157. [Abstract] [Full Text] [PDF]
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R. D. Smith, E. B. Babiychuk, K. Noble, A. Draeger, and S. Wray Increased cholesterol decreases uterine activity: functional effects of cholesterol alteration in pregnant rat myometrium Am J Physiol Cell Physiol, May 1, 2005; 288(5): C982 - C988. [Abstract] [Full Text] [PDF]
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M. Gallego, R. Setien, L. Puebla, M. d. C. Boyano-Adanez, E. Arilla, and O. Casis {alpha}1-Adrenoceptors stimulate a G{alpha}s protein and reduce the transient outward K+ current via a cAMP/PKA-mediated pathway in the rat heart Am J Physiol Cell Physiol, March 1, 2005; 288(3): C577 - C585. [Abstract] [Full Text] [PDF]
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J.-F. Jasmin, I. Mercier, R. Hnasko, M. W.-C Cheung, H. B Tanowitz, J. Dupuis, and M. P Lisanti Lung remodeling and pulmonary hypertension after myocardial infarction: pathogenic role of reduced caveolin expression Cardiovasc Res, September 1, 2004; 63(4): 747 - 755. [Abstract] [Full Text] [PDF]
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S. E Hardt and J. Sadoshima Negative regulators of cardiac hypertrophy Cardiovasc Res, August 15, 2004; 63(3): 500 - 509. [Abstract] [Full Text] [PDF]
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N. N Petrashevskaya, I. Bodi, S. E Koch, S. A Akhter, and A. Schwartz Effects of {alpha}1-adrenergic stimulation on normal and hypertrophied mouse hearts. Relation to caveolin-3 expression Cardiovasc Res, August 15, 2004; 63(3): 561 - 572. [Abstract] [Full Text] [PDF]
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P. Sonveaux, P. Martinive, J. DeWever, Z. Batova, G. Daneau, M. Pelat, P. Ghisdal, V. Gregoire, C. Dessy, J.-L. Balligand, et al. Caveolin-1 Expression Is Critical for Vascular Endothelial Growth Factor-Induced Ischemic Hindlimb Collateralization and Nitric Oxide-Mediated Angiogenesis Circ. Res., July 23, 2004; 95(2): 154 - 161. [Abstract] [Full Text] [PDF]
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Y. Ohsawa, H. Toko, M. Katsura, K. Morimoto, H. Yamada, Y. Ichikawa, T. Murakami, S. Ohkuma, I. Komuro, and Y. Sunada Overexpression of P104L mutant caveolin-3 in mice develops hypertrophic cardiomyopathy with enhanced contractility in association with increased endothelial nitric oxide synthase activity Hum. Mol. Genet., January 15, 2004; 13(2): 151 - 157. [Abstract] [Full Text] [PDF]
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 M. Yamaga, M. Sekimata, M. Fujii, K. Kawai, H. Kamata, H. Hirata, Y. Homma, and H. Yagisawa A PLC{delta}1-binding protein, p122/RhoGAP, is localized in caveolin-enriched membrane domains and regulates caveolin internalization Genes Cells, January 1, 2004; 9(1): 25 - 37. [Abstract] [Full Text] [PDF]
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B. Aravamudan, D. Volonte, R. Ramani, E. Gursoy, M. P. Lisanti, B. London, and F. Galbiati Transgenic overexpression of caveolin-3 in the heart induces a cardiomyopathic phenotype Hum. Mol. Genet., November 1, 2003; 12(21): 2777 - 2788. [Abstract] [Full Text] [PDF]
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I. P. Uray, J. H. Connelly, O.H. Frazier, H. Taegtmeyer, and P. J.A. Davies Mechanical unloading increases caveolin expression in the failing human heart Cardiovasc Res, July 1, 2003; 59(1): 57 - 66. [Abstract] [Full Text] [PDF]
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P. Ratajczak, T. Damy, C. Heymes, P. Oliviero, F. Marotte, E. Robidel, R. Sercombe, J. Boczkowski, L. Rappaport, and J.-L. Samuel Caveolin-1 and -3 dissociations from caveolae to cytosol in the heart during aging and after myocardial infarction in rat Cardiovasc Res, February 1, 2003; 57(2): 358 - 369. [Abstract] [Full Text] [PDF]
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A. Piech, C. Dessy, X. Havaux, O. Feron, and J.-L. Balligand Differential regulation of nitric oxide synthases and their allosteric regulators in heart and vessels of hypertensive rats Cardiovasc Res, February 1, 2003; 57(2): 456 - 467. [Abstract] [Full Text] [PDF]
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S. E. Woodman, D. S. Park, A. W. Cohen, M. W.-C. Cheung, M. Chandra, J. Shirani, B. Tang, L. A. Jelicks, R. N. Kitsis, G. J. Christ, et al. Caveolin-3 Knock-out Mice Develop a Progressive Cardiomyopathy and Show Hyperactivation of the p42/44 MAPK Cascade J. Biol. Chem., October 4, 2002; 277(41): 38988 - 38997. [Abstract] [Full Text] [PDF]
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 K. Dreja, M. Voldstedlund, J. Vinten, J. Tranum-Jensen, P. Hellstrand, and K. Sward Cholesterol Depletion Disrupts Caveolae and Differentially Impairs Agonist-Induced Arterial Contraction Arterioscler Thromb Vasc Biol, August 1, 2002; 22(8): 1267 - 1272. [Abstract] [Full Text] [PDF]
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 D. S. Park, S. E. Woodman, W. Schubert, A. W. Cohen, P. G. Frank, M. Chandra, J. Shirani, B. Razani, B. Tang, L. A. Jelicks, et al. Caveolin-1/3 Double-Knockout Mice Are Viable, but Lack Both Muscle and Non-Muscle Caveolae, and Develop a Severe Cardiomyopathic Phenotype Am. J. Pathol., June 1, 2002; 160(6): 2207 - 2217. [Abstract] [Full Text] [PDF]
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