EXPERIMENTAL STUDY
Regulation of myocardial ßARK1 expression in catecholamine-induced cardiac hypertrophy in transgenic mice overexpressing  1B-adrenergic receptors
Guido Iaccarino, MD*  ,
Janelle R. Keys, PhD,
Antonio Rapacciuolo, MD*,
Kyle F. Shotwell, BS,
Robert J. Lefkowitz, MD*   ,
Howard A. Rockman, MD* and
Walter J. Koch, PhD
* Medicine, Duke University Medical Center, Durham, North Carolina, USA
Surgery, Duke University Medical Center, Durham, North Carolina, USA
Biochemistry, Duke University Medical Center, Durham, North Carolina, USA
Howard Hughes Medical Institute, Duke University Medical Center, Durham, North Carolina, USA
Manuscript received November 17, 2000;
revised manuscript received March 15, 2001,
accepted April 24, 2001.
Reprint requests and correspondence: Dr. Walter J. Koch, Laboratory of Molecular Cardiovascular Biology, Duke University Medical Center, Room 472, MSRB, Research Drive, Durham, North Carolina 27710
koch0002{at}mc.duke.edu
 |
Abstract
|
|---|
OBJECTIVES
Using a transgenic mouse model of myocardial-targeted overexpression of the wild-type  1B adrenergic receptor (AR) (Tg43), we studied the role of the ßAR kinase (ßARK1) in the evolution of myocardial hypertrophy and its transition to heart failure (HF).
BACKGROUND
Increased myocardial expression of ßARK1 has been shown to be associated with HF and certain models of hypertrophy.
METHODS
Tg43 mice and their nontransgenic littermate controls were treated with the 1AR agonist phenylephrine (PE) for 3, 7 or 14 days to characterize the cardiac consequences.
RESULTS
Nontransgenic littermate control mice treated for 14 days with PE display cardiac hypertrophy with no increase in ßARK1 expression. However, Tg43 animals show a reduced tolerance to 14-day PE treatment, demonstrated by reduced survival and severe cardiac hypertrophy. Moreover, PE treatment for three and seven days in Tg43 mice resulted in an exaggerated hypertrophic response accompanied by significant cardiac biochemical abnormalities that are normally associated with HF, including fetal gene expression, reduced ßAR density and enhanced ßARK1 expression. We also found reduced myocardial stores of the sympathetic neurotransmitter neuropeptide Y.
CONCLUSIONS
These data suggest that PE-treated Tg43 mice have chronic activation of the cardiac sympathetic nervous system, which may be responsible for the appearance of apparent maladaptive hypertrophy with an evolution towards HF and sudden death. Thus, the cardiac phenotypes found in these mice are not the direct result of enhanced 1BAR signaling and suggest that ßARK1 is a key molecule in the transition of myocardial hypertrophy to HF.
|
Abbreviations and Acronyms
| | ANF | = atrial natriuretic factor | | AR | = adrenergic receptor | | ßARK1 | = ßAR kinase-1 | | CAM | = constitutively activated mutant | | cAMP | = cyclic adenosine monophosphate | | du | = densitometry units | | GPCR | = G protein-coupled receptor | | GRK | = G protein-coupled receptor kinase | | HF | = heart failure | | mRNA | = messenger ribonucleic acid | | NLC | = nontransgenic littermate control | | PE | = phenylephrine | | SERCA2a | = sarcoplasmic reticulum Ca++-ATPase | | Tg43 | = transgenic mice with cardiac targeted overexpression of the wild-type 1B-AR |
|
Myocardial hypertrophy is believed to be a mechanism of compensation that the heart activates to stabilize its performance in the presence of an injury or increased wall stress (1). Physiologic myocardial hypertrophy is often observed in athletes and can be considered an adaptive mechanism to support cardiac performance in the presence of an increased workload (2). However, when hypertrophy is induced be-
cause of a cardiac insult (i.e., cardiac overload), it often becomes maladaptive as it increases the metabolic needs of the myocardium and worsens cardiac performance.
Molecular mechanisms involved in the transition from hypertrophy to heart failure (HF) are not well understood. Several studies have demonstrated a role of signaling through heterotrimeric guanine nucleotide binding (G) proteins and their associated G protein-coupled receptors (GPCRs). Signaling through two G proteins, Gq and Gs, appears to be critically involved in both hypertrophy and failure. Signaling through Gq-coupled receptors such as the 1AR, the angiotensin II receptor and the endothelin I receptor has been shown to be quite effective at stimulating hypertrophy of the cardiac myocyte (3–5). Moreover, transgenic mice with myocardial-targeted overexpression of a constitutively activated mutant (CAM) of the 1BAR display modest cardiac hypertrophy (6). We have previously shown that Gq plays an obligatory role in the triggering of in vivo pressure overload ventricular hypertrophy (7). In addition, transgenic mice have also shown that overexpression of Gq itself, either a wild type or a CAM form, results in significant myocardial hypertrophy, which leads to a state of decompensation and HF (8,9).
In the failing heart, a constellation of abnormalities are present within the myocardial ßAR-Gs-cyclic adenosine monophosphate (cAMP) system. These include the downregulation of receptor density (10) and enhanced expression and activity of the ßAR kinase-1 (ßARK1) (or GRK2) (11), which is a G protein-coupled receptor kinase (GRK) that can phosphorylate and desensitize several GPCRs, including ßARs (12). Interestingly, ßARK1 may be one of the common links between hypertrophy and failure, as several studies in genetically engineered mice have found ßARK1 to be a critical regulator of cardiac function under normal conditions and also during myocardial hypertrophy and HF (12–17).
Importantly, one study linking ßARK1 to both Gq and Gs signaling in the heart has been carried out in transgenic mice with cardiac-specific overexpression of the wild-type 1BAR (Tg43) (18). In this study, enhanced in vivo signaling through the 1AR-Gq pathway, which is present in Tg43 mice, leads to significant desensitization of the myocardial ßAR system, which was found to be at least partially due to enhanced activity of ßARK1 (18). Interestingly, ßARK1 is not elevated in myocardial hypertrophy induced by chronic 1AR-agonist phenylephrine (PE) or in the CAM 1BAR transgenic mice (17). Moreover, it is not elevated in hypertrophic Gq transgenic mice (19). Thus, the Tg43 mice represent a unique and powerful model to study the role of ßARK1 in myocardial Gq and Gs coupled signal transduction. In the present study, we sought to investigate the consequences of PE treatment in Tg43 animals and to further investigate the role of ßARK1 in the cardiac biochemistry of these mice.
|
Methods
|
|---|
Animals, study design and pump implantation.
Tg43 mice were generated in our laboratory and have already been described (6,18). These mice have a cardiac 1AR density of  1.5 pmol/mg of membrane protein, which corresponds to 70-fold over nontransgenic littermate control (NLC) mice cardiac membrane 1AR density (20 fmol/mg of membrane protein). Tg43 and NLC mice three to six months old weighing 25 to 30 g were utilized in this study. The institutional animal usage committee at Duke University approved all animal procedures. Mini-osmotic pumps (Alzet model 2002, Palo Alto, California) were implanted as previously described (16,17). Pumps were set to deliver PE at 100 mg/kg/day or vehicle (phosphate-buffered saline) as a sham treatment. At 3, 7 and 14 days of treatment, individual heart weight-to-body weight ratios were calculated (mg/g) following removal of hearts from anesthetized animals. On day 7, a group of mice was anesthetized with a mixture of ketamine (10 mg/kg) and xylazine (0.5 mg/kg), and a polyethylene catheter (PE-10) was inserted into the right common carotid artery to measure systolic blood pressure as described (18).
Histology.
After 14 days, three animals from each group were anesthetized and the hearts were perfusion fixed, as described (17). Histological staining of myocytes was done with Masson’s trichrome by standard protocols (15).
Ligand binding assays and measurement of adenylyl cyclase activity.
Membrane fractions were prepared from hearts and 1AR or ßAR binding was carried out as described (16–18). ßAR responsiveness was assessed as the percent increase in cAMP production induced by the ßAR agonist isoproterenol compared with production under baseline conditions using methodology previously described (12,15).
ßARK1 immunoblotting and GRK activity assays.
Immunodetection of myocardial levels of ßARK1 was performed on detergent-solubilized extracts following immunoprecipitation, as we have previously described (16,17). G protein-coupled receptor kinase activity was assessed on cytosolic myocardial extracts using rhodopsin as a substrate as described (16,17).
Neuropeptide Y assays.
Neuropeptide Y was assessed on the clarified samples using a commercially available radioimmunoassay according to the manufacturer’s instructions (Peninsula Laboratories Inc., San Carlos, California).
Ribonucleic acid (RNA) extraction and Northern blot.
Ventricular tissue was separated from the atria under a dissecting microscope. Total ribonucleic acid was isolated using RNAzol (Biotecx, Houston, Texas), a one-step guanididium-based extraction solution. Northern blots were carried out as described (18).
Statistical analysis.
Effects of treatment on animal survival were estimated by a chi-square test. For multiple comparisons, two-way analysis of variance was used with one between (strain) and one within (treatment) factor. A one-way analysis of variance was also applied for comparisons between two groups. The null hypothesis was discarded when p < 0.05. Data are presented as mean ± SE.
|
Results
|
|---|
Heart weight-to-body weight ratios and histological measurements.
Chronic PE treatment was poorly tolerated by Tg43 mice. Survival was reduced in the transgenic mice to 40% after 14 days of treatment, which was statistically lower compared with PE treatment in NLC mice (Fig. 1A). Blood pressure measurements confirmed that Tg43 mice have lower systolic blood pressure compared with NLC mice (NLC, n = 10: 120 ± 5 mm Hg; TG43, n = 10: 104 ± 5 mm Hg; p < 0.05 vs. NLC) as previously described (18). Phenylephrine treatment increased systolic blood pressure in both NLC and Tg43 mice, which was still higher in NLC compared with Tg43 mice (NLC, n = 7: 168 ± 3 mm Hg; Tg43, n = 10: 140 ± 3 mm Hg; p < 0.05 vs. NLC).
Heart-to-body weight ratio was assessed at 3, 7 and 14 days as a measure of the hypertrophic response of the heart to PE treatment. A hypertrophic response to PE treatment was observed in NLC mice after 7 days with no further increase in heart size at 14 days of PE treatment (Fig. 1B). However, in the Tg43 mice treated with PE, a significant hypertrophic response was already present at 3 days, which was similar to that observed in NLC mice treated with PE for 7 or 14 days (Fig. 1B). In a subset of animals, we measured the heart-to-tibia-length ratio and after seven days of PE treatment, the heart-to-tibia-length ratio was significantly higher in Tg43 mice compared with NLC mice (Tg43: 9.3 ± 0.4, n = 9; NLC: 8.4 ± 0.1; n = 9; p < 0.05).
Histologically, sham-treated Tg43 mice had a normal macroscopic heart appearance, which was indistinguishable from NLC hearts. However, PE-treated Tg43 hearts showed pericardial and pleural effusions as well as cardiomegaly with global chamber dilation that was not seen in PE-treated NLC mice or sham-treated Tg43 animals (Fig. 2A). In >60% of hearts, the presence of organized thrombi in atria was observed (Fig. 2B). Upon microscopic examination, other differences in these models were found (Fig. 2C–F). Phenylephrine treatment of NLC mice did not cause significant necrosis, fibrosis or myofiber disarray compared with sham-treated NLC mice (Fig. 2C and D). Similarly, sham-treated Tg43 hearts presented with a normal microscopic appearance (Fig. 2E). However, 14 days of PE treatment in Tg43 mice caused increased collagen deposition (Fig. 2F). Because of the severity of the PE-response at 14 days and the lack of surviving animals in Tg43 mice, all further biochemical and functional assessments were performed after 7 days of treatment with PE. In Tg43 mice, seven days of PE treatment still led to exaggerated hypertrophic responses compared with PE-treated NLC mice (Fig. 1B).
Cardiac 1AR density.
As expected, PE induced a significant reduction in cardiac 1AR density in NLC mice because of agonist-mediated downregulation (sham: 23.9 ± 1.3 fmol/mg membrane protein, n = 5; PE: 14.5 ± 2.4 fmol/mg membrane protein, n = 5, p < 0.01). Interestingly, PE also induced a reduction in the transgenic 1AR density in Tg43 mice (sham: 1,560 ± 76 fmol/mg membrane protein, n = 6, PE: 1,172 ± 139 fmol/mg membrane protein, n = 6, p < 0.05).
Cardiac ßAR density and signaling.
We also examined the myocardial ßAR signaling system in the hearts of NLC and Tg43 mice treated with PE. Treatment for seven days with PE did not alter ßAR density in NLC mice (sham: 34.5 ± 2.4 fmol/mg membrane protein, n = 8; PE: 37.6 ± 3.4 fmol/mg membrane protein, n = 9, p = ns). ßAR density in sham-treated Tg43 mice was similar to NLC mice (34.6 ± 2.9 fmol/mg membrane protein, n = 9), however, PE-treated Tg43 animals displayed a significant reduction in myocardial ßAR density (25.2 ± 2.9 fmol/mg membrane protein, n = 9, p < 0.05 vs. sham-treated Tg43). ßAR signaling was assessed by measuring membrane adenylyl cyclase activity. Phenylephrine treatment of NLC and Tg43 mice did not alter membrane adenylyl cyclase activation either basally (NLC: sham: 39 ± 3 pmol/mg/min [n = 6]; PE: 34 ± 10 [n = 6], p = ns; Tg43; sham: 39 ± 3 pmol/mg/min [n = 12], PE: 40 ± 4 [n = 11], p = ns) or in response to 10 mM NaF (NLC; sham: 323 ± 25 pmol cAMP/mg/min [n = 6]; PE: 360 ± 18 [n = 6], p = ns; Tg43; sham: 290 ± 28 pmol/mg/min [n = 12], PE: 267 ± 22 [n = 11], p = ns), indicating that the content and activity of G proteins and that of adenylyl cyclase were not affected by the treatment. Phenylephrine did not affect ßAR responsiveness in NLC mice; however, in Tg43 animals the ßAR-mediated response to isoproterenol was impaired as compared with NLC mice as we have previously described (18), and PE treatment further worsened this response (Fig. 3A).
ßARK1 expression and activity.
One explanation for decreased ßAR responsiveness is enhanced activity of ßARK1. In NLC hearts, ßARK1 expression assessed by Western blot technique was not altered by PE treatment (sham: 31,061 ± 1,028 densitometry units [du], n = 7; PE: 32,267 ± 2,110 du, n = 6; p = not significant) confirming our previous observations in PE-treated wild-type mice (17). In sham-treated Tg43 animals, myocardial ßARK1 levels were similar to NLCs (26,024 ± 6,296 du, n = 11, p = not significant vs. NLC sham). Interestingly, unlike what was observed in PE-treated NLC mice, PE induced a twofold increase in the expression of this GRK in the hearts of Tg43 mice (Fig. 3B). This increased expression of ßARK1 resulted in a significant increase in myocardial GRK activity assessed in PE-treated Tg43 hearts compared with sham-treated Tg43 hearts (data not shown).
Cardiac neuropeptide Y levels.
Neuropeptide Y is co-released with norepinephrine from sympathetic nerve terminals and chronic firing of the sympathetic nervous system results in a faster tissue depletion of this neurotransmitter. Thus, a reduction in the cardiac content of neuropeptide Y is suggestive of chronic activation of the sympathetic nervous system in the heart (20). Cardiac levels of neuropeptide Y were similar between sham-treated and PE-treated NLC mice as well as sham Tg43 mice; however, in PE-treated Tg43 animals, the cardiac content of neuropeptide Y was significantly reduced by 20% (Fig. 4).
Cardiac expression of fetal genes.
To determine whether PE treatment altered the pattern of hypertrophy/HF gene expression in the hearts of NLC versus Tg43 mice, we assessed the expression of fetal genes that are modified in human and animal models of hypertrophy and HF such as atrial natriuretic factor (ANF) and skeletal -actin (21,22). We also examined the mRNA expression of the sarcoplasmic reticulum Ca++-ATPase (SERCA2a), which is reduced in experimental and human HF (23,24). Phenylephrine treatment in NLC mice did not affect the ventricular expression of ANF, skeletal -actin or SERCA2a (Fig. 5). We confirmed our previous findings that compared with NLC mice, Tg43 animals have increased levels of ventricular ANF expression (6,18), and made the novel observation that the expression of the skeletal -actin gene is also enhanced in Tg43 mouse hearts compared with NLC hearts (Fig. 5). In addition, no significant difference was observed in the levels of SERCA2a mRNA between sham-treated Tg43 and NLC hearts (Fig. 5). Interestingly, in Tg43 mice, no further increase in ANF and skeletal actin was detected after chronic PE treatment; however, there was a significant reduction in the expression of SERCA2a (Fig. 5).
|
Discussion
|
|---|
The present study focuses on the transition of myocardial hypertrophy towards HF in transgenic mice with cardiac overexpression of the wild-type 1BAR (Tg43) chronically treated with PE. Important to this model is that normally the overexpression of the 1BAR in the heart of Tg43 mice is not associated with negative effects on growth or mortality (18,25). The administration of PE to NLC mice results in moderate cardiac hypertrophy, whereas in Tg43 mice, chronic infusion of PE results in increased mortality associated with exaggerated cardiac hypertrophy, fibrosis and biochemical characteristics of HF.
Exaggerated hypertrophy and HF in Tg43 mice.
Interestingly, Tg43 mice have normal cardiac size. However, PE treatment caused exaggerated and severe hypertrophy, which is in contrast to the relatively benign effects of chronic PE administration in NLC mice. We found several changes in cardiac gene expression consistent with a decompensated state of myocardial function. These included a decrease in ventricular SERC2a mRNA levels and increased ventricular expression of ANF and skeletal -actin, which have previously been observed in several models of maladaptive hypertrophy and HF (21–24). Interestingly, untreated or sham-treated Tg43 mice already have significantly elevated ventricular mRNA levels of ANF and skeletal -actin, which is surprising because these mice do not normally present with cardiac hypertrophy (6,18). Moreover, ßAR density was decreased as well as adenylyl cyclase activity, which are characteristics of the failing heart. Importantly, PE treatment of NLC mice does not lead to these changes. Interestingly, Tg43 mice have normal ßAR density, but previously we did show that ßAR-mediated adenylyl cyclase activity was decreased because of heightened activity of ßARK1 (confirmed in this study) and Gi (18,25). This uncoupling was progressive in the present study because of the increased expression of ßARK1 as well as activity.
Overall, these signaling results suggest that as a consequence of 1AR overexpression, Tg43 hearts are "primed" for a hypertrophic response and chronic PE treatment exaggerates this response. However, this response not only leads to severe hypertrophy as a result of enhanced 1AR-Gq signaling but continues through apparent decompensation characterized by severe cardiac fibrosis, molecular changes consistent with HF and sudden death.
Enhanced sympathetic overdrive and ßARK1 expression.
Further supporting the conclusion that PE causes Tg43 mice to enter a state of decompensation and HF is the finding that cardiac stores of neuropeptide Y were reduced, indicating chronic activation of the sympathetic nervous system (20). This is a finding that was not evident in PE-treated NLC mice. Thus, it appears that deterioration of the state of Tg43 hearts after chronic PE exposure results in increased catecholamine outflow as a mechanism of adaptation and cardiac stimulation. This means that not only is 1AR-Gq signaling enhanced, but so is signaling through the ßAR-Gs pathway. Activation of the cardiac sympathetic nervous system plays an important role in the development of HF. One role of enhanced sympathetic nervous system activity that may be critically important in our current model is the induction of ßAR downregulation and uncoupling of ßAR signaling because of ßARK1 upregulation, which was present in the PE-treated Tg43 hearts. This does not occur in either PE treatment of NLC mice or in untreated Tg43 mice. Consistent with this hypothesis is the fact that we have previously shown that ßARK1 expression in the heart is increased after chronic catecholamine exposure (16,17).
The role of ßARK1 in the transition to HF.
Evidence is mounting that ßARK1 plays a critical role in the pathogenesis of HF (15,26–28). Increased ßARK1 expression precedes the development of frank cardiomyopathy in several experimental models of HF (26,28,29). Moreover, inhibiting the activity of myocardial ßARK1 appears to be a novel therapeutic target for improving the function of the failing heart. Transgenic mice overexpressing a peptide inhibitor of ßARK1 (ßARKct) have increased basal and catecholamine induced contractility (12). When these ßARKct expressing mice were crossbred with a genetic mouse model of HF induced by the knockout of the MLP gene, the resultant hybrid animals had normal cardiac size and function, demonstrating a HF "rescue" after ßARK1 inhibition (15). More recently, a study has been carried out in rabbits demonstrating the importance of ßARK1 in the pathogenesis of HF development following myocardial infarction where rabbits treated with a ßARKct adenovirus at the time of myocardial infarction had significantly delayed HF progression (26).
Concerning the present study, it is important to note that enhanced expression of ßARK1 is not a generalized phenomenon accompanying myocardial hypertrophy, because ßARK1 is not elevated in several other models of hypertrophy (13,17). These include transgenic models of cardiac hypertrophy attributable to p21ras overexpression (13) or CAM-1BAR overexpression (17). Moreover, as confirmed by the present study, NLC mice treated with PE had normal myocardial ßARK1 expression despite the presence of myocardial hypertrophy. Therefore, our present results add to the data supporting the hypothesis that myocardial ßARK1 expression is controlled by ßAR signaling. In this regard, we have demonstrated that, in the heart, changing the functional state of ßARs can specifically modulate ßARK1 expression (16). Chronic infusion of the ßAR agonist isoproterenol was associated with an increase in cardiac ßARK1 content whereas, reciprocally, inactivation of the ßARs by chronic administration of the ßAR antagonists atenolol and carvedilol resulted in reduction of ßARK1 and a subsequent increase in myocardial ßAR signaling (16). Of note, chronic stimulation of cardiac 1ARs does not alter ßARK1 expression in the hearts of wild-type mice (17). Thus, enhanced sympathetic nervous activity resulting from cardiac injury such as the severe (maladaptive) hypertrophy induced by PE treatment of Tg43 mice can enhance ßARK1 expression via ßAR signaling. In conclusion, our current results showing increased ßARK1 expression and activity in a model of exaggerated cardiac hypertrophy with increased mortality (PE-treated Tg43 mice) suggest that ßARK1 plays a unfavorable role in the evolution of cardiac hypertrophy and its transition to HF.
|
Footnotes
|
|---|
This work was supported in part by the National Institutes of Health grants HL-16037 (R.J.L.), HL-61690 (W.J.K.) and fellowships from the North Carolina Affiliate of the American Heart Association (G.I.) and Telethon Fondazione Onlus (G.I.). Robert J. Lefkowitz is an investigator at the Howard Hughes Medical Institute.
|
References
|
|---|
1. Grossman W, Jones D, McLaurin LP. Wall stress and patterns of hypertrophy in the human left ventricle. J Clin Invest. 1975;56:56–64[Medline]
2. Colan SD. Mechanics of left ventricular systolic and diastolic function in physiologic hypertrophy of the athlete’s heart. Cardiol Clin. 1997;15:355–372[CrossRef][Medline]
3. Simpson P. Norepinephrine-stimulated hypertrophy of cultured rat myocardial cells is an 1 adrenergic response. J Clin Invest. 1983;72:732–738[Medline]
4. Ito H, Hirata Y, Adachi S, et al. Endothelin-1 is an autocrine/paracrine factor in the mechanism of angiotensin II-induced hypertrophy in cultured rat cardiomyocytes. J Clin Invest. 1993;92:398–403[Medline]
5. Sadoshima J, Xu Y, Slayter HS, Izumo S. Autocrine release of angiotensin II mediates stretch-induced hypertrophy of cardiac myocytes in vitro. Cell. 1993;75:977–984[CrossRef][Medline]
6. Milano CA, Dolber PC, Rockman HA, et al. Myocardial expression of a constitutively active 1B-adrenergic receptor in transgenic mice induces cardiac hypertrophy. Proc Natl Acad Sci USA. 1994;91:10109–10113[Abstract/Free Full Text]
7. Akhter SA, Luttrell LM, Rockman HA, et al. Targeting the receptor-Gq interface to inhibit in vivo pressure overload myocardial hypertrophy. Science. 1998;280:574–577[Abstract/Free Full Text]
8. D’Angelo DD, Sakata Y, Lorenz JN, et al. Transgenic Gq overexpression induces cardiac contractile failure in mice. Proc Natl Acad Sci USA. 1997;94:8121–8126[Abstract/Free Full Text]
9. Mende U, Kagen A, Cohen A, et al. Transient cardiac expression of constitutively active Gq leads to hypertrophy and dilated cardiomyopathy by calcineurin-dependent and independent pathways. Proc Natl Acad Sci USA. 1998;95:13893–13898[Abstract/Free Full Text]
10. Bristow MR, Ginsburg R, Minobe W, et al. Decreased catecholamine sensitivity and ß-adrenergic-receptor density in failing human hearts. N Engl J Med. 1982;307:205–211[Medline]
11. Ungerer M, Parruti G, Bohm M, et al. Expression of ß-arrestins and ß-adrenergic receptor kinases in the failing human heart. Circ Res. 1994;74:206–213[Abstract/Free Full Text]
12. Koch WJ, Rockman HA, Samama P, et al. Cardiac function in mice overexpressing the ß-adrenergic receptor kinase or a ßARK inhibitor. Science. 1995;268:1350–1353[Abstract/Free Full Text]
13. Choi DJ, Koch WJ, Hunter JJ, Rockman HA. Mechanism of ß-adrenergic receptor desensitization in cardiac hypertrophy is increased ß-adrenergic receptor kinase. J Biol Chem. 1997;272:17223–17229[Abstract/Free Full Text]
14. Rockman HA, Choi DJ, Akhter SA, et al. Control of myocardial contractile function by the level of ß-adrenergic receptor kinase 1 in gene-targeted mice. J Biol Chem. 1998;273:18180–18184[Abstract/Free Full Text]
15. Rockman HA, Chien KR, Choi DJ, et al. Expression of a ß-adrenergic receptor kinase 1 inhibitor prevents the development of myocardial failure in gene-targeted mice. Proc Natl Acad Sci USA. 1998;95:7000–7005[Abstract/Free Full Text]
16. Iaccarino G, Tomhave ED, Lefkowitz RJ, Koch WJ. Reciprocal in vivo regulation of myocardial G protein-coupled receptor kinase expression by ß-adrenergic receptor stimulation and blockade. Circulation. 1998;98:1783–1789[Abstract/Free Full Text]
17. Iaccarino G, Dolber PC, Lefkowitz RJ, Koch WJ. ß-adrenergic receptor kinase-1 levels in catecholamine-induced myocardial hypertrophy: regulation by ß- but not 1-adrenergic stimulation. Hypertension. 1999;33:396–401[Abstract/Free Full Text]
18. Akhter SA, Milano CA, Shotwell KF, et al. Transgenic mice with cardiac overexpression of 1B-adrenergic receptors. In vivo 1-adrenergic receptor-mediated regulation of ß-adrenergic signaling. J Biol Chem. 1997;272:21253–21259[Abstract/Free Full Text]
19. Dorn GW 2nd, Tepe NM, Lorenz JN, et al. Low- and high-level transgenic expression of ß2-adrenergic receptors differentially affect cardiac hypertrophy and function in Gq- overexpressing mice. Proc Natl Acad Sci USA. 1999;96:6400–6405[Abstract/Free Full Text]
20. Anderson FL, Port JD, Reid BB, et al. Myocardial catecholamine and neuropeptide Y depletion in failing ventricles of patients with idiopathic dilated cardiomyopathy. Correlation with ß-adrenergic receptor downregulation. Circulation. 1992;85:46–53[Abstract/Free Full Text]
21. Izumo S, Nadal-Ginard B, Mahdavi V. Protooncogene induction and reprogramming of cardiac gene expression produced by pressure overload. Proc Natl Acad Sci USA. 1988;85:339–343[Abstract/Free Full Text]
22. Chien KR, Knowlton KU, Zhu H, Chien S. Regulation of cardiac gene expression during myocardial growth and hypertrophy: molecular studies of an adaptive physiologic response. FASEB J. 1991;5:3037–3046[Abstract]
23. Arai M, Alpert NR, MacLennan DH, et al. Alterations in sarcoplasmic reticulum gene expression in human heart failure. A possible mechanism for alterations in systolic and diastolic properties of the failing myocardium. Circ Res. 1993;72:463–469[Abstract/Free Full Text]
24. Okayama H, Hamada M, Kawakami H, et al. Alterations in expression of sarcoplasmic reticulum gene in Dahl rats during the transition from compensatory myocardial hypertrophy to heart failure. J Hypertens. 1997;15:1767–1774[CrossRef][Medline]
25. Grupp IL, Lorenz JN, Walsh RA, et al. Overexpression of 1B-adrenergic receptor induces left ventricular dysfunction in the absence of hypertrophy. Am J Physiol. 1998;275:H1338–H1350[Medline]
26. White DC, Hata JA, Shah AS, et al. Preservation of myocardial ß-adrenergic receptor signaling delays the development of heart failure after myocardial infarction. Proc Natl Acad Sci USA. 2000;97:5428–5433[Abstract/Free Full Text]
27. Lefkowitz RJ, Rockman HA, Koch WJ. Catecholamines, cardiac ß-adrenergic receptors, and heart failure. Circulation. 2000;101:1634–1637[Free Full Text]
28. Anderson KM, Eckhart AD, Willette RN, Koch WJ. The myocardial ß-adrenergic system in spontaneously hypertensive heart failure (SHHF) rats. Hypertension. 1999;33:402–407[Abstract/Free Full Text]
29. Cho MC, Rapacciuolo A, Koch WJ, et al. Defective ß-adrenergic receptor signaling precedes the development of dilated cardiomyopathy in transgenic mice with calsequestrin overexpression. J Biol Chem. 1999;274:22251–22256[Abstract/Free Full Text]
This article has been cited by other articles:
|
|
|
|
 
S. L. Belmonte and B. C. Blaxall
G Protein Coupled Receptor Kinases as Therapeutic Targets in Cardiovascular Disease
Circ. Res.,
July 22, 2011;
109(3):
309 - 319.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. Sorriento, G. Santulli, A. Fusco, A. Anastasio, B. Trimarco, and G. Iaccarino
Intracardiac Injection of AdGRK5-NT Reduces Left Ventricular Hypertrophy by Inhibiting NF-{kappa}B-Dependent Hypertrophic Gene Expression
Hypertension,
October 1, 2010;
56(4):
696 - 704.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. A. Woodcock, X.-J. Du, M. E. Reichelt, and R. M. Graham
Cardiac {alpha}1-adrenergic drive in pathological remodelling
Cardiovasc Res,
February 1, 2008;
77(3):
452 - 462.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. Most, H. Seifert, E. Gao, H. Funakoshi, M. Volkers, J. Heierhorst, A. Remppis, S. T. Pleger, B. R. DeGeorge Jr, A. D. Eckhart, et al.
Cardiac S100A1 Protein Levels Determine Contractile Performance and Propensity Toward Heart Failure After Myocardial Infarction
Circulation,
September 19, 2006;
114(12):
1258 - 1268.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. Barki-Harrington, C. Perrino, and H. A Rockman
Network integration of the adrenergic system in cardiac hypertrophy
Cardiovasc Res,
August 15, 2004;
63(3):
391 - 402.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. R. Keys, E. A. Greene, C. J. Cooper, S. V. Naga Prasad, H. A. Rockman, and W. J. Koch
Cardiac hypertrophy and altered {beta}-adrenergic signaling in transgenic mice that express the amino terminus of {beta}-ARK1
Am J Physiol Heart Circ Physiol,
November 1, 2003;
285(5):
H2201 - H2211.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. R. Keys, E. A. Greene, W. J. Koch, and A. D. Eckhart
Gq-Coupled Receptor Agonists Mediate Cardiac Hypertrophy Via the Vasculature
Hypertension,
November 1, 2002;
40(5):
660 - 666.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. F. Steinberg
G protein-coupled receptor kinases: gotta real kure for heart failure?
J. Am. Coll. Cardiol.,
August 1, 2001;
38(2):
541 - 545.
[Full Text]
[PDF]
|
|
|
|
Top
Abstract
Methods
2 test). (B) Heart-to-body weight ratio (mg/g) assessed after 3, 7 and 14 days of PE treatment in Tg
