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* Department of Surgery, Duke University Medical Center, Durham, North Carolina 27710
Center for Translational Medicine, Department of Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania 19107
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ABSTRACT |
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 TOP ABSTRACT I. Heart Failure and Sympathetic Nervous...II. Mouse Models to Study the Cardiac...REFERENCES |
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I. Heart Failure and Sympathetic Nervous System Signaling |
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TOPABSTRACTI. Heart Failure and Sympathetic Nervous...II. Mouse Models to Study the Cardiac...REFERENCES |
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The importance of sympathetic activity, via the catecholamines norepinephrine and epinephrine, in heart failure progression and mortality is well established (Cohn et al., 1984). At a cellular level, the catecholamines act upon the heart by binding to the adrenergic receptors (ARs), which are members of the superfamily of proteins known as the G protein-coupled receptors (GPCRs) (Caron and Lefkowitz, 1993). In the heart, norepinephrine principally binds to the 
1B- and ß1AR, while epinephrine is a ligand for both ß1- and ß2AR (Caron and Lefkowitz, 1993). The ß1AR is the most-abundant ßAR in the human heart, approaching 75% of the total number of receptors (Brodde, 1993). The ßARs are coupled primarily to the heterotrimeric G protein, Gs, to stimulate adenylyl cyclase activity. This association generates intracellular cyclic adenosine monophosphate (cAMP) and protein kinase A (PKA) activation, which regulate cardiac contractility and heart rate (Bristow et al., 1989). ß2ARs also can couple to the G protein, Gi, which can inhibit adenylyl cyclase activity and stimulate novel mitogen-activated protein kinase (MAPK) pathways in the heart through G and Gß
subunits (Rockman et al., 2002). Alternatively, binding of norepinephrine to the 1BAR elicits phospholipase C (PLC) activity via activation of the G protein, Gq, which is the principal G protein signaling pathway implicated in the hypertrophic response of the heart (Molkentin and Dorn, 2001).
Following agonist occupation of ARs, these GPCRs become substrates for regulation via G protein-coupled receptor kinases (GRKs), which phosphorylate activated receptor (Inglese et al., 1993). This phosphorylation facilitates binding of ß-arrestins, which sterically interferes with further coupling to G proteins, thus desensitizing and uncoupling the signal. The principal GRKs involved in intracellular signaling within the heart are GRK2 (or ß adrenergic receptor kinase 1, ßARK1), GRK3, and GRK5, all of which have specific GPCR selectivity in vivo in the heart (Eckhart et al., 2000). As will be detailed later, GRK activity in the heart appears to play a critical role, especially in heart failure. The generalized signaling pathways, their regulation, and outcomes in the heart are depicted in Figure 1.
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i is significantly upregulated, to dampen adenylyl cyclase activation (Feldman et al., 1988). Overall, these molecular adrenergic changes in the failing human heart (summarized in Table I) lead to a marked attenuation of cardiac ßAR signaling.
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2cAR gene, can act synergistically to increase the risk of heart failure in the black population (Small et al., 2002). These genetic studies, as well as recent heart failure drug trials, have indicated that there is still much to learn about alterations in the ßAR system during cardiac failure. This includes recent studies demonstrating significant improvement in survival with ßAR antagonist therapy in people with moderate and severe heart failure (Packer et al., 1996,2001). This is contra-indicative to the short-term effects of ß blockers (Epstein and Braunwald, 1966). The recent use of genetically engineered mice has provided unique experimental models for the study of cardiac adrenergic signaling alterations and the function of the normal and failing heart. |
II. Mouse Models to Study the Cardiac Adrenergic System |
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TOPABSTRACTI. Heart Failure and Sympathetic Nervous...II. Mouse Models to Study the Cardiac...REFERENCES |
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Using the myosin heavy chain (MHC) promoter to target gene expression to adult ventricular myocardium, mice that overexpress the ß1AR in the heart have been generated (Englhardt et al., 1999). These mice, with 5- to 15-fold overexpression compared to endogenous ßAR levels, exhibit a pathology that is consistent with chronic sympathetic stimulation, with a phenotype of dilated cardiomyopathy and heart failure (Englhardt et al., 1999). As will be detailed, this is in striking contrast to phenotypes observed with myocardial ß2AR overexpression.
2. The ß2AR
In contrast to the ß1AR knockout mice, gene disruption of the ß2AR does not appear to significantly alter cardiac physiology (Rohrer, 1998). This suggests that, under normal conditions, the ß2AR plays no major role in murine cardiac physiology. However, the ß2AR can significantly alter cardiac physiology when overexpressed. Transgenic MHC-ß2AR mice generated by the Lefkowitz laboratory had greater than 200-fold overexpression of endogenous ßARs. These mice possessed a biochemical and physiological phenotype that mimicked maximal ßAR myocardial signaling and function (Milano et al., 1994b). Surprisingly, even though these mice have enhanced heart rates and contractility from a young age, there is minimal pathology present, even in mice greater than 1 year of age (Koch et al., 2000). Furthermore, other transgenic mice with lower levels of overexpression (i.e., 30- to 50-fold) have similar characteristics (Turki et al., 1996). However, Liggett and colleagues (2000) have reported that a "transgene dose-response" for the ß2AR often can have delayed deleterious consequences, similar to what is observed with minimal ß1AR overexpression.
There appears to be significant Gi coupling in MHC-ß2AR mice, as demonstrated by studies utilizing the Gi inhibitory pertussis toxin (Xiao et al., 1999). These data contribute to recent findings demonstrating that signaling via ß1AR and ß2AR in the heart is fundamentally different (Rockman et al., 2002). The overall positive effects seen with transgenic ß2AR overexpression suggest that the use of genetic engineering to replace lost ßARs with the ß2AR in the failing heart may be therapeutic (Maurice et al., 1999). Consistent with this, we have found that cardiac ß2AR overexpression can "rescue" a mouse model of decompensated hypertrophy and heart failure due to cardiac Gq overexpression (Dorn et al., 1999). However, MHC-ß2AR mice were unable to rescue other mouse models of cardiomyopathy (Rockman et al., 1998b; Freeman et al., 2001). Moreover, ß2AR overexpression leads to functional deterioration of the heart, following induction of pressure overload (Du et al., 2000).
3. The 1BAR
Two lines of mice have been generated using the MHC promoter and the 1BAR. These mice express either the wild-type receptor or a constitutively active mutant of the 1BAR (CAM1BAR) (Akhter et al., 1997; Milano et al, 1994a). The CAM1BAR mice exhibit significant myocardial hypertrophy, suggesting that 1BAR activation can induce cardiac changes independent of hemodynamic influences (Milano et al., 1994a). In contrast, mice overexpressing the wild-type 1BAR do not develop an increase in heart size, despite displaying some biochemical characteristics of hypertrophy (Akhter et al., 1997). These mice, however, show a reduced tolerance to chronic 1BAR stimulation, indicating that they are primed for a hypertrophic response (Iaccarino et al., 2001). Interestingly, the MHC-1BAR transgenic mice have a decreased response to ßAR stimulation (Akhter et al., 1997), which appears to be mediated via an observed increase in ßARK1 expression and activity (Akhter et al., 1997; Iaccarino et al., 2001) and an activation of the sympathetic nervous system (Iaccarino et al., 2001). Thus, this mouse model has led to an elucidation of molecular cross-talk between the 1BAR and the ßAR systems in the heart. Finally, transgenic mice expressing the 1BAR under the control of its isogenic promoter exhibit myocardial hypertrophy and have a surprising loss of sympathetic activity (Zusic et al., 2001).
B. GENETIC ALTERATION OF CARDIAC G PROTEIN EXPRESSION
1. Gs
Transgenic mice overexpressing the stimulatory G protein Gs in the heart have been generated and characterized (Gaudin et al., 1995). These mice exhibit enhanced responsiveness to catecholamines and develop cardiomyopathy as they age (Geng et al., 1999), in a model reminiscent of human heart failure. Interestingly, the phenotype can be rescued by chronic administration of a ßAR blocker (Asai et al., 1999), suggesting that this phenotype, at least partially, mimics chronic sympathetic nervous system activation and enhanced ßAR signaling.
2. Gi
Targeted disruption of Gi2 or Gi3 (the major Gi subtypes in myocardium) in mice revealed that there appears to be no significant role for Gi signaling in basal cardiac function or in the response to ßAR stimulation in the normal heart (Jain et al., 2001). In contrast to these knockout results, expression of a novel Gi-coupled receptor in the heart resulted in a large decrease in myocardial force, suggesting that defects in the Gi signaling pathway may contribute to the development of cardiac pathology (Redfern et al., 1999; Baker et al., 2001). These results are consistent with the upregulation of Gi, contributing to human heart failure and the uncoupling of the ßAR system (Feldman et al., 1988).
3. Gq
Dorn and colleagues have described transgenic mice overexpressing Gq in the heart (D’Angelo et al., 1997). MHC-Gq mice with 4-fold overexpression have cardiac hypertrophy and alterations in all of its molecular markers (D’Angelo et al., 1997). These animals, like the 1BAR overexpressors, display abrogated AR function. Crossbreeding the Gq mice with transgenic mice that had 200-fold overexpression of the ß2AR worsened the Gq phenotype (Dorn et al., 1999). However, a line of ß2AR mice with only 30-fold overexpression of the receptor rescued the cardiac hypertrophy (Dorn et al., 1999), suggesting that selective, controlled ßAR enhancement may be beneficial. At higher levels of Gq expression in the transgenic mice, severe heart failure and early death was observed, with a component of increased myocyte apoptosis (Adams et al., 1998).
4. Gq Inhibition
Due to the importance of Gq signaling in the development of cardiac hypertrophy, our laboratory set out to selectively inhibit this pathway in the heart. To achieve this, a specific peptide inhibitor consisting of the last 54 amino acids of the Gq (GqI) was developed and studied (Akhter et al., 1998). This GqI peptide targets the receptor-Gq interface, competitively inhibiting Gq activation while not affecting Gs or Gi signaling (Akhter et al., 1998). Transgenic mice expressing the GqI peptide in the heart were shown to have attenuated responses to Gq-coupled receptor stimulation (Akhter et al., 1998). When these animals were subjected to an experimental model of pressure overload cardiac hypertrophy, expression of the GqI peptide in the heart significantly inhibited development of the hypertrophic phenotype (Akhter et al., 1998). Thus, this study identified Gq activation as the final common trigger for pressure overload hypertrophy. More recently, these mice have shown resistance to heart failure following chronic hypertrophic stimulus (Esposito et al., 2002), suggesting that Gq-class specific inhibition is a novel strategy to prevent ventricular dysfunction in conditions of chronic hypertrophic stress.
C. MANIPULATION OF CARDIAC GRK EXPRESSION
1. ßARK1
The importance of ßARK1 (GRK2) in the cardiovascular system is clearly noted by the severe cardiac malformations and embryonic death observed following ßARK1 gene ablation (Jaber et al., 1996). The findings suggest a possible role for ßARK1 in the normal migration and differentiation of myocardial cells during heart development. Heterozygous ßARK1 knockout mice with 50% less ßARK1 expression and activity in myocardium have no developmental abnormalities (Rockman et al., 1998b). Transgenic mice that overexpress ßARK1 in the heart due to the use of the MHC promoter have an attenuated response to catecholamine stimulation with desensitized ßARs (Koch et al., 1995). This was a significant finding, as it represents the first demonstration that ßARK1 could cause the functional uncoupling of ßARs in vivo. Furthermore, these mice demonstrate that the upregulation of ßARK1 seen in human heart failure may have significance and contribute to the pathogenesis of ventricular dysfunction. Contractile responses to angiotensin II also are abrogated in MHC-ßARK1 transgenic mice, suggesting that ßARK1 may be important in other receptor systems in the heart (Rockman et al., 1996). Interestingly, ßARK1 overexpression has no effect on cardiac 1BAR signaling, demonstrating GRK-GPCR selectivity in vivo (Eckhart et al., 2000).
2. Inhibition of ßARK1
Since ßARK1 activity is increased in heart failure and appears to play a role in uncoupling of ßARs in the heart, we have studied the physiological consequences of ßARK1 inhibition. To do this, a specific peptide inhibitor consisting of the last 194 amino acids of the ßARK1 (ßARKct) was developed and studied (Koch et al., 1993). The ßARKct contains the Gß binding domain and competes with endogenous ßARK1 for Gß-mediated membrane translocation, a process required for ßARK1 activation on activated GPCRs (Koch et al., 1993). When the ßARKct was expressed in the hearts of transgenic mice under the control of the MHC promoter, cardiac physiology was altered in reciprocal fashion to that seen with ßARK1 overexpression (Koch et al., 1995). The ßARKct mice have enhanced cardiac function at baseline and an augmented response to catecholamines (Koch et al., 1995). Importantly, using a hybrid transgenic mouse strategy where ßARK1 overexpression and ßARKct expression occurred in vivo simultaneously, we have shown that the ßARKct is, indeed, inhibiting cardiac ßARK1 activity (Akhter et al., 1999).
The phenotypes of the ßARK1 and the ßARKct mice are consistent with our hypothesis that this GRK plays a critical role in cardiac function and potentially in cardiac pathologies. Interestingly, heterozygous ßARK1 knockout mice also have a phenotype of enhanced cardiac function (Rockman et al., 1998b), demonstrating that lowering ßARK1 expression or its activity can have profound in vivo effects on cardiac contractility. Moreover, hybrid mice that express the ßARKct in the heart and are heterogeneous for ßARK1 gene ablation have even-greater enhancement of cardiac function (Rockman et al., 1998b).
In addition to heart failure, enhanced ßARK1 expression and activity has been shown to be indicative of several models of cardiac hypertrophy (Koch et al., 2000). Enhanced ßARK1 activity in the hypertrophied heart has been shown to be responsible for the loss of ßAR inotropic reserve seen in this pathological condition (Choi et al., 1997). To study the inhibition of ßARK1 during hypertrophy, we used a novel transgenic mouse model. The ßARKct was targeted to the heart using the cardiac ankyrin repeat protein (CARP) promoter, which turns off during adulthood. However CARP belongs to a family of fetal genes, such as atrial natiuretic factor (ANF), that can be reactivated in adult ventricular myocardium by stress. CARP-ßARKct mice lose ßARKct expression after 3 weeks of life and adult mice do not have enhanced contractility (Manning et al., 2000). However, following induction of pressure overload hypertrophy, expression of the ßARKct is seen once again in the myocardium, resulting in improved ßAR responsiveness and cardiac function (Manning et al., 2000).
3. Cardiac Transgenic Studies with GRK3 and GRK5
Following the profound effects seen with ßARK1 manipulation in the hearts of transgenic mice, we studied the physiological consequences of GRK3 and GRK5 overexpression. These two GRKs are found normally in the heart but their overall role in cardiac signaling is not well understood, although GRK5 has been found to be upregulated in some animal models of heart failure (Ping et al., 1997; Vinge et al., 2001). Unlike ßARK1, both GRK3 and GRK5 homozygous knockout mice are viable with no overt cardiac phenotype (Wess, 2000). Overexpression of these GRKs in the heart has, however, led to unexpected and interesting results that have uncovered novel aspects of GRK regulation in vivo in the heart. GRK3 (also known as ßARK2) previously was thought to be an isozyme of ßARK1, since it is highly homologous and appeared to have the same in vitro GPCR activity (Benovic et al., 1991; Freedman et al., 1995). However, when MHC-GRK3 mice were generated and studied, there were no signaling alterations in the cardiac ßAR system (Iaccarino et al., 1998a). This was the first demonstration in vivo that GRK3 was different from ßARK1, with a unique GPCR specificity profile. Further investigation revealed that thrombin signaling in the heart was uncoupled in these mice, demonstrating that the thrombin receptors are in vivo substrates for GRK3 (Iaccarino et al., 1998a). The difference in these GRKs may lie in the Gß binding regions, which is the area between GRK3 and ßARK1 that is the most divergent (Muller et al., 1997). Thus, there may be selective GPCR-mediated translocation of these GRKs. In hybrid transgenic mice with different GRKs overexpressed along with the 1BAR, it was found that GRK3 is also the primary kinase for desensitization of this AR in the heart (Eckhart et al., 2000).
GRK5, which is the second-highest expressing GRK in the heart, is not regulated by Gß and thus would be expected to have different receptor substrates in the heart. However, like ßARK1 overexpressing mice, MHC-GRK5 transgenic mice had severely blunted ßAR inotropic responses in vivo in the heart, demonstrating that this GRK also could desensitize cardiac ßARs (Rockman et al., 1996). These mice exhibited GPCR substrate selectivity, compared to ßARK1, as responses to angiotensin II were not altered, whereas this Gq-coupled receptor system was desensitized in mice overexpressing ßARK1 (Rockman et al., 1996). GRK5 also has some activity against cardiac 1BARs, again demonstrating a difference with ßARK1 (Eckhart et al., 2000). The overall significance of the findings that GRK5 may be altered in heart failure is not clear at this time but obviously could have important implications.
III. ßARK1 Inhibition and Rescue of Murine Models of Heart Failure
One interesting area where this research has led us is to investigate whether inhibition of ßARK1 activity could be a novel therapeutic strategy for improving function of the failing heart. Over the last few years, this has become possible to study in the mouse, as murine models of cardiomyopathy have been described, many of which have important manifestations of the human condition. These models have been the result of a specific gene deletion in the mouse or cardiac-specific overexpression of a heart failure-inducing transgene. Powerful information can be generated by cross-breeding MHC-ßARKct mice and various heart failure models to test the hypothesis that Gß-ßARK1 inhibition could be beneficial. Simply studying the cardiac phenotype of these novel hybrid mice could give an answer and provide information on the role of ßARK1 and GRK activity in the pathogenesis of the various heart failure etiologies, specific for the different models. We have studied six different heart failure models with ßARKct mice and, for the most part, have seen overwhelming rescue. Table II summarizes our findings over the last 3–4 years using this novel genetic approach; some of the more-important findings are detailed in the next paragraph.
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As detailed in Table II, cardiac ßARKct expression also has rescued other models of heart failure, including one with cardiac-targeted overexpression of a mutant form of the MHC gene (HCM) that is associated with human hypertrophic cardiomyopathy (Freeman et al., 2001). Interestingly, expression of the ßARKct in the Gq mice had no effect on the Gq phenotype, unlike the ß2AR (Dorn et al., 1999). In the Gq model of decompensated cardiac hypertrophy, ßARK1 is not upregulated, suggesting that the ßARKct is acting specifically to inhibit GRKs. However, the exact mechanism of the ßARKct may involve sequestration of Gß from other signaling pathways, such as those involved in the activation of phosphoinositide-3 kinase (PI3K) (Naga Prasad et al., 2000,2001) and IK,Achchannels (Clapham and Neer, 1997). The contribution of these other potential Gß effects to the salutary effects of ßARKct in heart failure remains to be determined. Finally, the therapeutic benefit of the ßARKct may involve enhanced signaling through other GPCRs such as angiotensin II receptors.
IV. Hypertension, the Adrenergic Pathway, and Heart Failure
The American Heart Association suggests that the presence of hypertension or high blood pressure in a patient doubles that person’s risk for developing heart failure. In essential hypertension, elevated blood pressure has been associated with increased sympathetic output (Mark, 1990), suggesting that the catecholamines and associated adrenergic pathways may be involved in this pathology. It also implicates hypertension as a potential primary component in the development of heart failure. Indeed, studies have shown that agents that reduce blood pressure, no matter what the mechanism, all appear to eventually reverse hypertrophy (Testa et al., 1996; Anker et al., 1997).
We previously discussed the importance of Gq signaling in cardiac hypertropy and heart failure. As was detailed, transgenic mice that express the GqI peptide inhibitor of Gq can prevent the development of hypertrophy and heart failure in a pressure-overload model (Akhter et al., 1998; Espositio et al., 2002). To study the potential contribution of the vascular system and its associated alterations in blood pressure to this hypertrophic response, we developed a line of trangsenic mice that express GqI in vascular smooth muscle cells under the control of the SM22 promoter (Keys et al., 2002). Following chronic Gq agonist administration, we observed an attenuation of mean arterial blood pressure and an inhibition of cardiac hypertrophy in the transgenic mice with vascular GqI expression (Keys et al., 2002). In contrast — and somewhat unexpectedly — when the GqI was expressed in the heart, neither hypertension nor hypertrophy was inhibited (Keys et al., 2002). These findings suggest that, during hypertension, the vascular system is the principal determinant of cardiac hypertrophy, rather than direct stimulation of the heart itself.
Interestingly, impairment of the vascular ßAR system has been shown in human and animal models of hypertension (Feldman, 1990; Brodde and Michel, 1992). More specifically, elevations in ßARK1 expression have been found in lymphocytes of hypertensive patients (Gros et al., 1997,1999). Recently, we generated transgenic mice that express ßARK1 in the vascular smooth muscle, again using the SM22 promoter (Eckhart et al., 2002b). These mice display attenuated vascular ßAR signaling, an increase in mean blood pressure, and develop cardiac hypertrophy (Eckhart et al., 2002b). This again implicates the adrenergic system in hypertrophy–and, in particular, cardiovascular ßARK1 activity — which also proposes a link between hypertension and heart failure.
IV. Conclusion
The development of transgenic mouse models has provided a broader understanding of the physiological impact of individual proteins during heart failure. Overall, through our efforts detailed herein and those from other laboratories around the world, there are currently at least 75 genetically altered mouse models available to study the role of particular signaling systems in the heart (Chu et al., 2002). This review has focused on the adrenergic signaling pathway under normal conditions and during heart failure. It is evident that transgenic mice have given us insight into the role of adrenergic system in the heart that otherwise would not have been possible. In the future, we hope that this knowledge may yield novel therapeutic interventions for the treatment of cardiac disease. In fact, adenoviral-mediated delivery of the ßARKct and ß2AR to larger animal models of heart failure has resulted in beneficial effects (White et al., 2000; Shah et al., 2001; Tevaearai et al., 2002), suggesting that gene-therapy strategies may, indeed, target these AR abnormalities in heart failure in the coming years and offer new hope to patients suffering from this disease of epidemic proportions.
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