(Circulation. 2001;103:1311.)
© 2001 American Heart Association, Inc.
Basic Science Reports |
In Vivo Ventricular Gene Delivery of a ß-Adrenergic Receptor Kinase Inhibitor to the Failing Heart Reverses Cardiac Dysfunction
From the Departments of General and Thoracic Surgery (A.S.S., D.C.W., S.E., A.P.K., R.E.L., D.D.G., W.J.K.) and Medicine and Biochemistry (K.W., R.J.K.) and the Howard Hughes Medical Institute, Duke University Medical Center, Durham, NC.
Correspondence to Walter J. Koch, PhD, Box 2606, MSRB Room 471, Duke University Medical Center, Durham, NC 27710. E-mail koch0002{at}mc.duke.edu
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Abstract |
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Background—Genetic manipulation to reverse molecular abnormalities associated with dysfunctional myocardium may provide novel treatment. This study aimed to determine the feasibility and functional consequences of in vivo ß-adrenergic receptor kinase (ßARK1) inhibition in a model of chronic left ventricular (LV) dysfunction after myocardial infarction (MI).
Methods and Results—Rabbits underwent ligation of the left circumflex (LCx) marginal artery and implantation of sonomicrometric crystals. Baseline cardiac physiology was studied 3 weeks after MI; 5x1011 viral particles of adenovirus was percutaneously delivered through the LCx. Animals received transgenes encoding a peptide inhibitor of ßARK1 (Adeno-ßARKct) or an empty virus (EV) as control. One week after gene delivery, global LV and regional systolic function were measured again to assess gene treatment. Adeno-ßARKct delivery to the failing heart through the LCx resulted in chamber-specific expression of the ßARKct. Baseline in vivo LV systolic performance was improved in Adeno-ßARKct–treated animals compared with their individual pre–gene delivery values and compared with EV-treated rabbits. Total ß-AR density and ßARK1 levels were unchanged between treatment groups; however, ß-AR–stimulated adenylyl cyclase activity in the LV was significantly higher in Adeno-ßARKct–treated rabbits compared with EV-treated animals.
Conclusions—In vivo delivery of Adeno-ßARKct is feasible in the infarcted/failing heart by coronary catheterization; expression of ßARKct results in marked reversal of ventricular dysfunction. Thus, inhibition of ßARK1 provides a novel treatment strategy for improving the cardiac performance of the post-MI heart.
Key Words: gene therapy • receptors • heart failure • signal transduction
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Molecular abnormalities associated with and implicated in the pathogenesis of ventricular dysfunction and heart failure (HF) present appealing targets for cardiac gene therapy. In particular, genetic manipulation of myocardial ß-adrenergic receptor (ß-AR) signaling offers a powerful way to alter myocardial function and represents a potential target that has recently elicited much attention.1 ß-AR signaling abnormalities in the compromised and dysfunctional human heart have been well characterized and include a downregulation of ß-ARs (specific for the ß1-AR subtype), uncoupling of second-messenger systems, and an upregulation of the ß-adrenergic receptor kinase (ßARK1).2 3 ßARK1 (also known as GRK2) is a member of the G-protein–coupled receptor kinase (GRK) family that phosphorylates agonist-occupied receptors, including cardiac ß-ARs, triggering desensitization.4 5 Recent evidence has revealed that enhanced ßARK1-mediated desensitization of myocardial ß-ARs represents a maladaptive change in the failing heart,6 and thus ßARK1 activity is a novel therapeutic target for potentially reversing ventricular dysfunction in cardiac disease states.
Importantly, ßARK1 has been found to be a critical
regulator of myocardial
function.5 The expression and
GRK activity of ßARK1 in the heart has been found to be significantly
elevated in human3 and animal
models7 8 9
of HF, hypertrophy,10 and
ischemia.11 Studies in
genetically engineered mice have demonstrated the utility of ßARK1
inhibition; expression of a ßARK1-inhibitory peptide has prevented HF
as the result of the knockout of the muscle LIM protein
gene.8 The inhibitor of
ßARK1 (ßARKct) is a peptide composed of the carboxyl-terminal
194–amino acid residues of ßARK1, which competes with endogenous
ßARK1 for binding to the membrane-embedded ß
-subunits of
activated heterotrimeric G-proteins, a process required for ßARK1
activation.5 12
Recently, catheter-based methods have enabled in vivo adenovirally mediated gene transfer to normal and hypertrophied myocardium.6 13 14 These invasive methods in rats and rabbits have been developed to deliver transgenes globally to the beating heart in vivo. In a recent study, Adeno-ßARKct was delivered globally to rabbit hearts at the time of the surgical induction of myocardial infarction (MI).6 Interestingly, the acute inhibition of myocardial ß-AR desensitization in the infarcted heart prevented the development of HF, demonstrating that the loss of ß-AR coupling in the failing heart may not be solely an adaptive and protective mechanism but can contribute to the pathogenesis of HF.6
In this study, we have taken a unique approach in that the ßARKct transgene was not delivered to the heart until it was compromised in order to determine whether inhibition of ßARK1 activity in the failing heart could reverse physiological left ventricular (LV) dysfunction. We have recently demonstrated in vivo adenovirally mediated transgene delivery in a ventricular-specific manner through selective percutaneous coronary catheterization and gene delivery.15 This technique was used in the present study, in which delivery of the ßARKct transgene into the left circumflex coronary artery (LCx) targets LV-specific expression and the untreated RV can serve as an internal control to test the efficacy of the transgene. ßARKct gene delivery to a dysfunctional heart is a critical step in validating ßARK1 inhibition as a potential therapy for HF.
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Methods |
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Adenoviral Constructs
The construction, production, and purification of adenoviral constructs with a second-generation E1/E4-deleted, replication-deficient adenovirus have previously been described.6 Three transgenes were used: ßARKct (Adeno-ßARKct), the marker transgene ß-Galactosidase (Adeno-ßGal), and an empty viral construct (EV).
Model of MI and Physiology
All animals received humane care, in compliance with
guidelines prepared by the National Institutes of Health and according
to protocols approved by Duke University. Adult male New Zealand White
rabbits (
3 kg) were used in the study. Animals underwent a
thoracotomy and implantation of sonomicrometric crystals along the
minor axis of the LV as
described.16 In 21 animals,
a large marginal branch of the LCx was ligated as
described,6 whereas in 5
animals (the sham group), a prolene suture was passed around the vessel
without ligation. Physiological assessment was made 3 weeks after MI to
assess baseline cardiac function before gene delivery. A 2.5F
micromanometer (Millar Inc) was placed into the LV cavity through the
carotid artery under fluoroscopic guidance, and a 22-gauge
angiocatheter was placed into the jugular vein. The sonomicrometric
crystals and micromanometer were coupled to a PC-based data acquisition
system (Physiological Systems Inc), and LV pressure (P) as well as
segmental length (l) was obtained at baseline in spontaneously
breathing animals. All hemodynamic data were derived from the average
of 20 steady-state cardiac
cycles.16 Regional segmental
length was used to determine systolic shortening (SS) as a measure of
LV systolic function with the equation
SS=(led-les)/led,
where led and les
represent end-diastolic and end-systolic length,
respectively.16 SS was then
expressed as a percentage of pre–gene delivery values. Infarct size
was measured as we have
described6 and did not
significantly differ among treatment groups (data not shown). The mean
infarct size on all animals was 40±10% of the
LV.
Intracoronary Gene Transfer
After the 3-week post-MI physiological assessment,
5x1011 total viral particles (tvp) of
adenovirus in 2 mL of PBS was injected into the LCx after percutaneous
catheterization, as we have previously
described.15 All rabbits
received methylprednisolone (5.0 mg/kg IM per day) for 2 days after
adenoviral delivery to limit the acute adenovirally mediated
inflammatory response. Seven days after gene delivery (and 4 weeks
after MI), cardiac function was studied in each rabbit as
above.
Determination of Myocardial Transgene
Expression and ß-AR Signaling
To assess the efficacy of gene transfer to the
infarcted rabbit heart, Adeno-ßGal was delivered to the post-MI LCx
as above. After excision of the heart, transverse cross sections of
myocardium at the midpapillary level were obtained for histological
analysis and X-gal staining as
described.14 15
To assess ßARKct transgene expression, ventricular RNA was isolated,
and Northern blot analysis was performed by standard methods previously
described.5 6
Determination of cardiac ß-AR density and membrane adenylyl cyclase
(AC) activity were performed on myocardial sarcolemmal membranes with
standard methods previously
described.6 14 15
Statistical Analysis
All data are expressed as mean±SEM. In vivo
hemodynamic data were compared by means of a paired Student’s
t test. Unpaired comparisons
were made by ANOVA. For all analyses, a value of
P<0.05 was considered to be
statistically significant.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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In Vivo Intracoronary Delivery of Adenoviral Transgenes to Infarcted Rabbit Heart
LCx-mediated delivery of Adeno-ßGal (5x1011 tvp) to rabbits 3 weeks after MI resulted in robust expression of the transgene as determined by X-gal staining. Positive cardiomyocytes stained blue, and, as expected, were confined to the areas of the LV served by the vascular bed of the LCx (Figure 1A
). Neither the septum nor the right ventricle (RV)
stained blue, confirming a selective intracoronary delivery, and
limited expression was found in the infarct zone
(Figure 1A). Delivery of 5x1011
tvp of Adeno-ßARKct through the LCx to infarcted rabbit hearts also
displayed an LV-specific distribution of the transgene mRNA. A
representative Northern blot demonstrating ßARKct transgene
expression is shown in
Figure 1B.
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Improvement of LV Dysfunction in Post-MI Hearts
After Adeno-ßARKct Delivery
The functional consequences of selective intracoronary
delivery of Adeno-ßARKct in post-MI rabbits was determined by
sonomicrometry and micromanometry catheterization. Animals were
initially studied 3 weeks after LCx ligation to assess baseline post-MI
function. We have previously shown that 3 weeks after infarction is the
time at which hemodynamic dysfunction and other signs of HF are clearly
evident.6 7 The
function of the LV in post-MI rabbits 3 weeks after LCx ligation as
assessed by SS with sonomicrometry crystals was profoundly depressed
compared with rabbits that underwent sham operation. MI rabbits that
were subsequently randomized to receive Adeno-ßARKct or EV had a
significant 68% decrease in LV SS compared with sham animals
(Figure 2A). LV end-diastolic pressure (EDP) was
significantly elevated in MI animals compared with sham (data not
shown), as has been previously described in this
model.6 7
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P<0.05 vs pre–gene delivery values; 
P<0.05 vs Adeno-ßARKct. B, Percent change in SS 1 week after gene delivery in EV-treated and Adeno-ßARKct–treated animals. *P<0.05 vs pre–gene delivery values.
MI rabbits with significant regional and global LV
dysfunction were treated by LCx catheterization with
5x1011 tvp of Adeno-ßARKct or EV and were
allowed to progress for 1 more week. Regional LV function was then
measured, and Adeno-ßARKct–treated rabbits showed marked and
significant improvement in LV SS compared with values obtained just
before gene delivery
(Figure 2A
). This near 100% improvement in LV SS was not
seen in EV-treated MI rabbits. In fact, these rabbits displayed a
significant decrease in LV SS 1 week after gene delivery
(Figure 2B). In a separate subset of 3-week postinfarcted
rabbits (n=5), 2D echocardiography was
performed6 before and 1 week
after Adeno-ßARKct delivery. LV function as assessed by percent
fractional shortening was significantly improved by ßARK1 inhibition
(before, 19.5±1% versus after, 23±2%,
P<0.05,
t test).
In vivo hemodynamics were evaluated by LV intracavitary
pressure with micromanometer
catheterization.6 7
There was a small improvement in contractility as measured by LV
dP/dtmax, after Adeno-ßARKct delivery that did
not reach statistical significance
(Table).
However, after ßARKct expression, peak systolic blood pressure was
significantly increased in the failing hearts after Adeno-ßARKct
treatment, which was also significantly greater that in than EV-treated
MI rabbits
(Table).
Interestingly, both LV EDP and HR did not significantly change after
Adeno-ßARKct delivery, whereas both of these parameters worsened
(increased) in animals that received EV.
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Molecular ß-AR Signaling Changes Induced by
ßARKct Expression in Infarcted Heart
Three weeks after LCx ligation, a biventricular
alteration of ß-AR signaling was observed similar to that seen in
other forms of HF. Samples from noninfarcted areas of the LV as well as
RV samples from MI rabbit hearts had a decrease in total ß-AR
density.
Figure 3 contains this data. Sham animals had normal LV
ß-AR density of 65 fmol per mg membrane protein, whereas LV and RV
samples from 3-week post-MI rabbits that received Adeno-ßARKct or EV
had significantly downregulated ß-ARs. In addition to ß-AR density
changes, post-MI rabbit hearts had elevated ßARK1 expression (data
not shown) and uncoupled AC signaling (see below) compared with sham
control hearts. These alterations in ßARK1 levels and ß-AR
signaling are consistent with those seen in our original study
characterizing this rabbit HF
model.7 One week after
Adeno-ßARKct or EV delivery to the infarcted LV, there was no
significant change in ßARK1 expression (data not shown).
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Despite no change in ß-AR density among treated animals,
desensitization of ß-ARs in the infarcted LV was significantly
reversed after Adeno-ßARKct delivery. Shown in
Figure 4A is baseline and isoproterenol-stimulated AC
activity found in myocardial membranes isolated from post-MI hearts 1
week after EV or Adeno-ßARKct delivery. As shown, ß-AR–stimulated
AC activity was minimal in the infarcted hearts treated with EV,
demonstrating severe uncoupling, whereas hearts expressing the ßARK1
inhibitor had restored ß-AR responsiveness
(Figure 4A). In fact, as shown in
Figure 4B, the ß-AR responsiveness in ßARKct-treated LVs
was greater than what we found in membranes from noninfarcted sham LVs.
The AC data are also interesting from the point of view that they
clearly illustrate the LV-selective gene targeting of the ßARKct
caused by LCx-mediated delivery. As shown in
Figure 4B, the ß-AR responsiveness in RV membranes is not
restored, as in the LV. The EV-treated infarcted hearts have a similar
loss of isoproterenol-stimulated AC activity in both the RV and LV
compared with sham values, demonstrating global loss of ß-AR function
in these MI rabbit hearts
(Figure 4B).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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This study reports two novel findings. The first is that in vivo percutaneous intracoronary gene delivery to the infarcted heart is feasible. Moreover, this gene delivery method can specifically target the failing LV. Second, we have demonstrated that adenovirally mediated myocardial delivery of the ßARKct transgene reverses ß-AR signaling abnormalities and LV systolic dysfunction after MI. We have clearly demonstrated that a percutaneous delivery system, selectively catheterizing a coronary artery, can effectively deliver adenoviral transgenes to the failing heart after MI.
Importantly, in our model, gene delivery was accomplished through the LCx 3 weeks after the ligation of a marginal branch of the same artery. Transgene expression 1 week later was robust and widespread throughout the noninfarcted area of the LV. It is important to emphasize that the model used in this study does not completely represent ischemic heart disease as seen clinically. It is limited in that a single artery is ligated with a variable amount of infarcted myocardium, resulting in a range of LV dysfunction. However, we have previously demonstrated that this model recapitulates the biventricular signaling abnormalities seen in HF.7 Furthermore, the power of the study design is that each animal serves as its own control, with an untreated RV as an additional source for comparison in individual animals.
Biochemically, the expression of ßARKct in the LV improved
ß-AR signaling in the treated LV but not in the RV, which is a
powerful demonstration of the ventricular specificity of our gene
delivery methodology. In addition, LV AC activity in the
Adeno-ßARKct–treated animals was significantly higher than in
EV-treated control rabbits, indicating that ß-AR desensitization was
attenuated as a consequence of ßARKct expression. Interestingly,
ßARKct transgene expression did not alter ßARK1 levels between the
LV and RV of Adeno-ßARKct–treated rabbits. This suggests that
expression of ßARKct at 1 week does not reverse the central
neurohormonal or local mechanical stimulus responsible for ßARK1
upregulation. Importantly, it provides further evidence that the
improvement in AC activity and in vivo LV function is due to active
inhibition of ßARK1 by the ßARKct rather than a relative decrease
in ßARK1 expression. Of course, because the ßARKct acts through
Gß inhibition, other signaling events mediated by Gß may also
contribute to the positive therapeutic effects seen in HF. Moreover,
other receptor systems that are targets for ßARK1, in addition to
ß-ARs, may be involved.
We used both sonomicrometry and micromanometry to assess LV function in vivo in this small-animal model. Adeno-ßARKct–treated animals had significant improvements in sonomicrometrically derived measures of LV systolic function. Moreover, there was a trend toward increased LV dP/dtmax. Although all of the parameters are load-sensitive, the regional improvement in function as demonstrated by SS suggests a contractile benefit of ßARKct expression. In fact, a significant decrease in LV SS was seen in control animals treated with the EV, suggesting an underlying decline in function secondary to catheterization or progression of dysfunction after 1 week of adenovirus delivery. The use of LV dP/dt as a measure of global LV function may be limited by the variation in infarct size and may be more sensitive to loading conditions in this model than in normal myocardium. LV EDP did not significantly change in Adeno-ßARKct–treated animals compared with EV-treated control rabbits, in which it increased further between 3 and 4 weeks after MI. This demonstrates that in MI rabbits not treated with the ßARKct, LV dysfunction is progressing.
It bears mentioning that ventricular failure involves a myriad of receptor systems and abnormalities. It is unlikely that a single transgene can reverse all of the dysfunction and completely rescue the failing heart. However, of paramount importance is finding an efficacious transgene that is safe and does not ultimately damage myocardium. Perhaps more importantly, our catheter-based technique lends itself to other models of failure and hypertrophy and other intriguing questions may be answered with this technology. Thus, in addition to targeting myocardial ß-AR signaling through ßARK1 inhibition, as in this study, or exogenously increasing ß2-AR density,14 15 other worthwhile gene targets exist. The most promising appear to be manipulating myocardial Ca2+ handling through the sarcoplasmic reticulum ATPase13 or phospholamban.18 An additional target that has recently emerged is manipulation of K+ channels in the cardiac sarcolemma, in attempts to alter repolarization abnormalities present in the failing heart.19
Several lines of evidence point toward the actions of ßARK1 being critically involved in the pathogenesis of HF. These include the fact that myocardial ßARK1 expression is elevated in chronic human HF,3 contributing to the desensitization and downregulation of cardiac ß-ARs.2 3 Because ßARK1 expression and activity in the heart is also elevated in several animal models of disease,6 7 8 9 10 11 we have recently used transgenic mice with myocardium-specific expression of ßARKct to further characterize the role of ßARK1 in heart disease. The potential therapeutic usefulness of ßARK1 inhibition was demonstrated in the prevention of HF in a genetic mouse model of cardiomyopathy.8 This was accomplished by cross-breeding of the ßARKct transgenic mouse with a mouse HF model induced by "knockout" of the muscle LIM protein gene.8 Before the current study, adenovirally mediated transfer of the ßARKct transgene to failing cardiomyocytes isolated from rabbits in HF resulted in the reversal of ß-AR signaling abnormalities.17 In addition, we have recently delivered Adeno-ßARKct to rabbit hearts at the time of LCx ligation and MI and found that ßARK1 inhibition prevented the ß-AR signaling abnormalities present acutely after MI and thereby significantly delayed the development of HF.6
This study provides unique insight into one approach for therapeutic cardiac gene therapy. Adenoviral vectors encoding ßARKct have allowed us to test the hypothesis that genetic manipulation of ß-adrenergic signaling in adult myocardium may improve systolic function in the setting of acquired LV dysfunction. No reports have previously examined this question. Our model demonstrates that noninfarcted yet dysfunctional myocardium may be rescued at a molecular level. Thus, ßARK inhibition may represent a novel form of molecular ventricular assistance.
The fact that ß-AR signaling is severely impaired in the
failing heart no doubt provokes hyperactivity of the sympathetic
nervous system; thus, a pathological cycle is perpetuated. Our
hypothesis is that by relieving a brake on the system (ie, ßARK1),
cardiac function can be improved, which can also chronically lead to
the dampening of sympathetic overdrive, thus reversing the vicious
cycle. Therefore, unlike ß-agonists that can improve contractility
acutely but further uncouple ß-ARs through chronic stimulation,
inhibition of ßARK1 begins to return ß-ARs to a more normal state
of signaling. This may not only lead to the acute improvement in
cardiac performance but also can allow the compromised myocardium to
recover from the chronic bombardment of catecholamines, which
characterize the decompensated state. The present study, demonstrating
the effectiveness of the ßARKct in reversing functional signaling
abnormalities in the post-MI heart, adds weight to our recent study
demonstrating that inhibition of ßARK1 at the time of LCx ligation
can prevent acute ß-AR signaling abnormalities and delay the
development of HF. Both studies support our hypothesis that ßARK1 is
an important HF target.20
This novel therapeutic strategy can be approached either through gene
therapy with the ßARKct or through the development of pharmaceutical
inhibitors of the ßARK1 Gß
interaction.
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Acknowledgments |
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This work was supported in part by National Institutes of Health grants HL-16037 (R.J.L.), HL-59533 (W.J.K.), and HL-56205 (W.J.K.) and a Grant-in-Aid from the American Heart Association (W.J.K.). R.J. Lefkowitz is an Investigator of the Howard Hughes Medical Institute. The authors thank the Genzyme Corporation (Framingham, Mass) for preparation and purification of some of the Adeno-ßARKct.
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Footnotes |
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Dr Shah and Dr White contributed equally to this work.
Received August 4, 2000; revision received October 2, 2000; accepted October 2, 2000.
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References |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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1. Lefkowitz RJ, Rockman HA, Koch WJ. Catecholamines, cardiac "ß" adrenergic receptors, and heart failure. Circulation. 2000;101:1634–1637.
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 D. Leosco, G. Rengo, G. Iaccarino, A. Filippelli, A. Lymperopoulos, C. Zincarelli, F. Fortunato, L. Golino, M. Marchese, G. Esposito, et al. Exercise training and beta-blocker treatment ameliorate age-dependent impairment of beta-adrenergic receptor signaling and enhance cardiac responsiveness to adrenergic stimulation Am J Physiol Heart Circ Physiol, September 1, 2007; 293(3): H1596 - H1603. [Abstract] [Full Text] [PDF]
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 H. Ly, Y. Kawase, R. Yoneyama, and R. J. Hajjar Gene Therapy in the Treatment of Heart Failure Physiology, April 1, 2007; 22(2): 81 - 96. [Abstract] [Full Text] [PDF]
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 J. M. Eltit, A. A. Garcia, J. Hidalgo, J. L. Liberona, M. Chiong, S. Lavandero, E. Maldonado, and E. Jaimovich Membrane Electrical Activity Elicits Inositol 1,4,5-Trisphosphate-dependent Slow Ca2+ Signals through a Gbeta{gamma}/Phosphatidylinositol 3-Kinase {gamma} Pathway in Skeletal Myotubes J. Biol. Chem., April 28, 2006; 281(17): 12143 - 12154. [Abstract] [Full Text] [PDF]
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 M. A. Nordlie, L. E. Wold, B. Z. Simkhovich, C. Sesti, and R. A. Kloner Molecular Aspects of Ischemic Heart Disease: Ischemia/Reperfusion-Induced Genetic Changes and Potential Applications of Gene and RNA Interference Therapy Journal of Cardiovascular Pharmacology and Therapeutics, March 1, 2006; 11(1): 17 - 30. [Abstract] [PDF]
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 J. M. Vicencio, C. Ibarra, M. Estrada, M. Chiong, D. Soto, V. Parra, G. Diaz-Araya, E. Jaimovich, and S. Lavandero Testosterone Induces an Intracellular Calcium Increase by a Nongenomic Mechanism in Cultured Rat Cardiac Myocytes Endocrinology, March 1, 2006; 147(3): 1386 - 1395. [Abstract] [Full Text] [PDF]
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P. K. Pandalai, J. M. Lyons, J. Y. Duffy, K. M. McLean, C. J. Wagner, W. H. Merrill, J. M. Pearl, and S. A. Akhter Role of the {beta}-adrenergic receptor kinase in myocardial dysfunction after brain death J. Thorac. Cardiovasc. Surg., October 1, 2005; 130(4): 1183 - 1189. [Abstract] [Full Text] [PDF]
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H. Tachibana, S. V. Naga Prasad, R. J. Lefkowitz, W. J. Koch, and H. A. Rockman Level of {beta}-Adrenergic Receptor Kinase 1 Inhibition Determines Degree of Cardiac Dysfunction After Chronic Pressure Overload-Induced Heart Failure Circulation, February 8, 2005; 111(5): 591 - 597. [Abstract] [Full Text] [PDF]
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M. L. Williams, J. A. Hata, J. Schroder, E. Rampersaud, J. Petrofski, A. Jakoi, C. A. Milano, and W. J. Koch Targeted {beta}-Adrenergic Receptor Kinase ({beta}ARK1) Inhibition by Gene Transfer in Failing Human Hearts Circulation, April 6, 2004; 109(13): 1590 - 1593. [Abstract] [Full Text] [PDF]
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 L. G. MELO, A. S. PACHORI, D. KONG, M. GNECCHI, K. WANG, R. E. PRATT, and V. J. DZAU Gene and cell-based therapies for heart disease FASEB J, April 1, 2004; 18(6): 648 - 663. [Abstract] [Full Text] [PDF]
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S. M. Emani, A. S. Shah, M. K. Bowman, D. C. White, S. Emani, D. D. Glower, and W. J. Koch Right ventricular targeted gene transfer of a {beta}-adrenergic receptor kinase inhibitor improves ventricular performance after pulmonary artery banding J. Thorac. Cardiovasc. Surg., March 1, 2004; 127(3): 787 - 793. [Abstract] [Full Text] [PDF]
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C. Ibarra, M. Estrada, L. Carrasco, M. Chiong, J. L. Liberona, C. Cardenas, G. Diaz-Araya, E. Jaimovich, and S. Lavandero Insulin-like Growth Factor-1 Induces an Inositol 1,4,5-Trisphosphate-dependent Increase in Nuclear and Cytosolic Calcium in Cultured Rat Cardiac Myocytes J. Biol. Chem., February 27, 2004; 279(9): 7554 - 7565. [Abstract] [Full Text] [PDF]
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G. W. Dorn II and J. D. Molkentin Manipulating Cardiac Contractility in Heart Failure: Data From Mice and Men Circulation, January 20, 2004; 109(2): 150 - 158. [Full Text] [PDF]
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 J.R. Keys and W.J. Koch The Adrenergic Pathway and Heart Failure Recent Prog. Horm. Res., January 1, 2004; 59(1): 13 - 30. [Abstract] [Full Text]
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 P. Le Corvoisier, H.-Y. Park, K. M. Carlson, D. A. Marchuk, and H. A. Rockman Multiple quantitative trait loci modify the heart failure phenotype in murine cardiomyopathy Hum. Mol. Genet., December 1, 2003; 12(23): 3097 - 3107. [Abstract] [Full Text] [PDF]
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D. J. Nusz, D. C. White, Q. Dai, A. M. Pippen, M. A. Thompson, G. B. Walton, C. J. Parsa, W. J. Koch, and B. H. Annex Vascular rarefaction in peripheral skeletal muscle after experimental heart failure Am J Physiol Heart Circ Physiol, October 1, 2003; 285(4): H1554 - H1562. [Abstract] [Full Text] [PDF]
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 J. A. Hata and W. J. Koch Phosphorylation of G Protein-Coupled Receptors: GPCR Kinases in Heart Disease Mol. Interv., August 1, 2003; 3(5): 264 - 272. [Abstract] [Full Text] [PDF]
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 H. T. Tevaearai, G. B. Walton, A. D. Eckhart, J. R. Keys, and W. J. Koch Donor heart contractile dysfunction following prolonged ex vivo preservation can be prevented by gene-mediated {beta}-adrenergic signaling modulation Eur. J. Cardiothorac. Surg., November 1, 2002; 22(5): 733 - 737. [Abstract] [Full Text] [PDF]
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M. C. LaPointe, X.-P. Yang, O. A. Carretero, and Q. He Left ventricular targeting of reporter gene expression in vivo by human BNP promoter in an adenoviral vector Am J Physiol Heart Circ Physiol, October 1, 2002; 283(4): H1439 - H1445. [Abstract] [Full Text] [PDF]
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J. Kim, A. D. Eckhart, S. Eguchi, and W. J. Koch beta -Adrenergic Receptor-mediated DNA Synthesis in Cardiac Fibroblasts Is Dependent on Transactivation of the Epidermal Growth Factor Receptor and Subsequent Activation of Extracellular Signal-regulated Kinases J. Biol. Chem., August 23, 2002; 277(35): 32116 - 32123. [Abstract] [Full Text] [PDF]
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 J. Huang and C. D. Kontos Inhibition of Vascular Smooth Muscle Cell Proliferation, Migration, and Survival by the Tumor Suppressor Protein PTEN Arterioscler Thromb Vasc Biol, May 1, 2002; 22(5): 745 - 751. [Abstract] [Full Text] [PDF]
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J. Huang and C. D. Kontos PTEN Modulates Vascular Endothelial Growth Factor-Mediated Signaling and Angiogenic Effects J. Biol. Chem., March 22, 2002; 277(13): 10760 - 10766. [Abstract] [Full Text] [PDF]
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S. M. Emani, A. S. Shah, D. C. White, D. D. Glower, and W. J. Koch Right ventricular gene therapy with a {beta}-adrenergic receptor kinase inhibitor improves survival after pulmonary artery banding Ann. Thorac. Surg., November 1, 2001; 72(5): 1657 - 1661. [Abstract] [Full Text] [PDF]
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