Cardiovascular Research

Cardiovascular Research 1999 44(1):5-9; doi:10.1016/S0008-6363(99)00211-4
© 1999 by European Society of Cardiology

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Copyright © 1999, European Society of Cardiology

Signal transduction during cardiac hypertrophy: the role of G_q, PLC βI, and PKC

Thunder Jalili¹, Yasuchika Takeishi and Richard A Walsh^*

Department of Medicine, Case Western Reserve University, 11100 Euclid Avenue, Cleveland, OH 44106-5029, USA

^* Corresponding author. Tel.: 1-216-844-3293; fax: 1-216-844-3145 raw19{at}po.cwru.edu

Received 6 November 1998; accepted 29 March 1999

	1 Introduction

Top 1 Introduction 2 G protein-coupled receptor... 3 Conclusions References

 
Currently the precise biochemical pathogenesis of cardiac hypertrophy remains unclear. A great deal of investigation has been directed toward the examination of various signal transduction pathways that are thought to be involved in stimulating this process. In particular, the signaling pathways that use heterotrimeric G protein-coupled receptors have been the focus for many investigations. This review will focus on the function of the G_q family of proteins and its downstream effectors during cardiac hypertrophy. Hypertrophy is the final common pathway for a variety of insults to the normal cardiovascular system. Many mechanical and hormonal stimuli such as hypertension, valve disorders, and ischemic events, can produce a hypertrophic response. These pathologic stimuli cause an increase in the workload placed upon the heart resulting in hypertrophy and remodeling that has been observed at the myocyte [1] and the gross anatomical level. Current thought suggests that the hypertrophic response is a compensatory mechanism that allows normal cardiac function against a gradient of increasing workload. If the pathologic stimulus is sufficiently intense or prolonged, a period of failure characterized by impaired function, dilation of the left ventricle, and pulmonary congestion ensues.

Recently, experiments using cardiac specific transgenesis to investigate G protein-mediated mechanisms of cardiac hypertrophy have yielded novel information that may give us cause to re-evaluate our traditional stratification of hypertrophic states [2]. It is important to evaluate these results along with other conventional and transgenic models so that we can develop a more comprehensive understanding of this complex disease.

	2 G protein-coupled receptor signaling

Top 1 Introduction 2 G protein-coupled receptor... 3 Conclusions References

 
Heterotrimeric G protein-coupled receptors serve to convey an extracellular biochemical signal to intracellular effectors. These receptors are heptahelical structures with extracellular, transmembrane, and intracellular domains coupled to specific G proteins which are comprised of three (, β, ) subunits. When the G protein complex is in the inactive state, guanosine diphosphate (GDP) is bound to the subunit while the β dimer acts to stabilize this conformation (Fig. 1). After ligand binding, a conformational shift in the G protein complex occurs resulting in a decreased affinity of the subunit for GDP. The active state for G begins when GDP is exchanged for GTP, followed by disassociation of the subunit from the rest of the G protein complex. G proteins serve to activate a number of effectors such as adenylate cyclase, phospholipase C β (PLC β), and ion channels [3]. Gβ can also act as a signal transducer as demonstrated by its ability to stimulate PLC activity in vitro [4]. Deactivation of G occurs when GTP is hydrolyzed to GDP, a process mediated by the intrinsic GTPase activity of G, as well as GTPase activating proteins (GAPs). G with bound GDP will re-associate with the β dimer, forming a heterotrimeric complex that is poised for re-activation by the next extracellular signal.

View larger version (23K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 1 G coupled receptor activation of protein kinase C (PKC) in cardiac muscle. When extracellular agonists such as endothelin I, angiotensin II, or phenylephrine bind to the G protein-coupled receptor complex a conformational shift in the G protein complex results in the displacement of GDP and binding of GTP to the Gq subunit. Upon GTP binding, Gq is released from the complex and activates phospholipase C βI (PLC βI). A class of molecules known as regulators of G protein signaling (RGS) can activate the intrinsic GTPase activity of Gq to hydrolyze GTP to GDP, resulting in Gq inactivation and re-association with the β dimer. PLC βI catalyzes the hydrolysis of phosphotidylinositol bisphosphate (PIP2) into diacylglycerol (DAG) and inositol triphosphate (IP3). IP3 binds to the IP3 receptor on the sarcoplasmic reticulum (SR) and causes release of calcium into the cytosol. The IP3 receptor itself comprises about 5% of the calcium channels on the SR whereas the ryanodine receptor (RYR) comprises about 95% of these channels in heart muscle. Calcium released into the cytosol by the IP3 receptor binds to the calcium sensitive isoforms of PKC (PKC , βI, βII, ) resulting in translocation of PKC to the cell membrane. Once PKC is translocated to the cell membrane it is activated by DAG and begins to phosphorylate various cell proteins hypothesized to play a critical role in cardiac hypertrophy such as transcription factors, Na+/H+ exchanger, myofilament proteins, and voltage-dependent calcium channels.

 
The activation potential of G proteins can be influenced by several factors including half-life (which is dependent on its intrinsic GTPase activity), post-translational modification, extrinsic modification of GTPase activity, and G_q expression levels present in the cell [3]. GTPase activating proteins (GAPs) also serve to increase the intrinsic GTPase activity of G. Recently, a new class of GAPs has been characterized that may play a critical role in regulating G protein activity. These are named regulators of G protein signaling (RGS). To date eight RGS subtypes have been identified that stimulate G-mediated GTP hydrolysis, all with differential specificity directed toward the various G proteins [5].

There are currently four classes of G proteins identified; _s, _i, ₁₂, and _q [6]. The G_s family consists of _s and _olf, that stimulate adenylate cyclase. The G_i family includes _i-1, _i-2, and _i-3 that are inhibitors of adenylate cyclase, _z and _o that regulate potassium and calcium channels, and _t-1, _t-2, and _gust that activate cyclic GMP phosphodiesterase. Members of the G₁₂ family of ₁₂ and ₁₃ are postulated to regulate the Na⁺/H⁺ exchanger. The G_q family of proteins consisting of G_q, G₁₁, G₁₄, G₁₅, and G₁₆ are activators of PLC β.

2.1 The role of G_q signaling in cardiac hypertrophy
Previous experiments using cultured neonatal cardiomyocytes have demonstrated that both G protein agonists such as angiotensin II, as well as mechanical stretch, can stimulate a hypertrophic response [7–9]. These early studies implicated a role for the involvement of this G protein signaling pathway in the development of cardiac hypertrophy. The recent revolution in cardiac specific mouse transgenesis has facilitated more detailed in vivo experiments aimed at delineating the role of G protein mediated signaling in cardiac hypertrophy.

Over expression of G_q in the mouse has been used to assess its role in cardiac hypertrophy. D’Angelo et al. [10] produced three separate lines of transgenic mice with various levels of cardiac specific overexpression of G_q. This study found cardiac hypertrophy at the whole heart level, recapitulation of the fetal gene program, and increased mortality in a gene dose dependent manner. The downstream signaling protein PKC was also activated in this model. Furthermore, echocardiographic and invasive high fidelity micromanometer hemodynamic studies revealed significant contractile depression associated with the cardiac hypertrophy, and this contractile dysfunction was observed at the myocyte level as well. This model, however, presented some unique aspects in its hypertrophic phenotype. In spite of whole heart hypertrophy, there was no appreciable left ventricular (LV) hypertrophy present during G_q overexpression. This presents an interesting scenario where LV myocyte dysfunction and contractile depression exists without concomitant LV hypertrophy. This unique aspect was explored further when experimental banding of the G_q overexpression mouse was performed. Superimposing hemodynamic stress (via constriction of the aorta) upon a mouse that had basal cardiac dysfunction lead to the development of classic decompensated cardiac hypertrophy characterized by LV hypertrophy, pulmonary congestion and continued impaired contractile parameters [2]. Furthermore, it was also observed that the greater the level of G_q expression, the quicker the onset of decompensated heart failure. Thus, it appears that even though G_q overexpression produces a unique compromised type of cardiomyopathy that is neither compensated or decompensated, it can progress to classic decompensation with the superimposition of hemodynamic stress.

Inhibiting G_q signaling may be an approach to prevent cardiac hypertrophy from occurring through pressure overload stimuli. This has been investigated in mice using cardiac-specific overexpression of a peptide fragment derived from the carboxy terminus of G_q that can effectively block G_q receptor coupling [11]. Pressure overload, induced by constriction of the aorta, results in substantially less cardiac hypertrophy in transgenic mice overexpressing the G_q inhibitor peptide than in wild type controls. G_q inhibitor mice developed a moderate degree of hypertrophy that fell between the level of hypertrophy observed in non surgically treated G_q controls and surgically banded wild types. Incomplete attenuation of pressure overload induced hypertrophy in G_q inhibitor mice suggests that other signaling pathways, perhaps tyrosine kinase mediated, may also be playing a role in the development of cardiac hypertrophy. These transgenic mice also had a blunted response to direct ventricular injection of the G protein agonists angiotensin II, endothelin I, and phenylephrine. In contrast, studies using mice with targeted ablation of the angiotensin II type 1A (AT1) receptor revealed that pressure overload continued to induce cardiac hypertrophy [12,13]. This result, however, suggests the presence of unknown, yet redundant pathways that may mediate a hypertrophic response.

In broadly evaluating these studies one can conclude that G_q receptor coupling via several extracellular signals directly stimulates the hypertrophic response, but there are clearly other cell signaling systems unrelated to G_q that play a role in the development of hypertrophy. Furthermore, it can be inferred that G_q signaling, independent of hemodynamic load leads to contractile dysfunction at the myocyte level.

2.2 Signaling through G_q activates phospholipase c β (PLC β) and protein kinase C (PKC)
Four types of PLC β exist; PLC β1, PLC β2, PLC β3, and PLC β4. Sensitivity for activation by G_q is greatest with PLC β1 and PLC β3 [3]. In the heart, PLC β1 is the major isoform expressed [4] while PLC β3 is expressed in all tissues [3]. PLC β2 has been found in smooth muscle, brain tissue, and liver [14]. PLC β4 appears to exist only in the retina [15] and specific areas of the brain [16]. Once active, these isoforms of PLC β cleave membrane bound phosphotidylinositol bisphosphate (PIP₂) into diacylglycerol (DAG) and inositol 1,4,5-triphosphate (IP₃). These products serve to activate various downstream protein kinase C (PKC) isoforms as described in more detail in the following section.

It is interesting to note that G_q activity can be influenced by the concentration of PLC β1 as well. In vitro systems using G_q in reconstituted lipid vesicles have demonstrated that the rate of GTP hydrolysis increases up to 50-fold following addition of PLC β1 [17]. In addition, G_q-mediated GTP hydrolysis was observed to be at one half of maximal velocity when PLC βI levels were 2-fold greater than G_q, and at maximal velocity when PLC βI levels were 20–30-fold greater than G_q [17]. Thus, a negative feedback loop may exist such that high concentrations of PLC βI can reduce G_q activity by increasing the rate of GTP hydrolysis.

The products of PIP₂ hydrolysis, DAG and IP₃, are potent activators of protein kinase C (PKC). PKC, an important enzyme family of serine–threonine kinases, plays a role in the cellular response to hormones, growth factors and neurotransmitters such as endothelin I, angiotensin II, and 1-adrenoreceptors [18,19], all of which are signaled by G_q coupled receptors. Mammalian PKCs are comprised of 11 isoforms: conventional isoforms responsive to calcium (, βI, βII, ); novel isoforms that lack the calcium binding site (, , , ); and atypical isoforms that do not respond to phorbol esters (, , µ) [20]. PKC isoforms consist of a single polypeptide chain that contains an amino-terminal regulatory region and a carboxy-terminal kinase domain [21]. All PKC isoforms contain a highly conserved carboxy-terminal kinase domain (C3 and C4). PKC isoforms differ in their amino-terminal regulatory regions. The regulatory region of PKCs contains an autoinhibitory domain, the C1 domain, and the C2 domain. The C1 domain binds DAG and phorbol esters, and the C2 domain binds acidic phospholipids and Ca²⁺. Activation of PKC requires the removal of the autoinhibitory domain from the active site. IP₃ induces calcium release from sarcoplasmic reticulum stores, resulting in the translocation of the Ca²⁺ sensitive PKC. Following translocation to the membrane, DAG (mimicked by phorbol esters) activates conventional and novel PKC isoforms. Once active, PKC modulates activity of transcription factors (c-jun and fos) and gene expression [22,23], voltage-dependent calcium channels [24], Na⁺/H⁺ exchanger [25], sarcoplasmic reticular proteins [26], and myofilament proteins troponin I and troponin T [27,28].

It has been demonstrated that the PKC activation process involves binding with a group of proteins termed RACKs (receptors of activated C-kinase). These proteins are specific for various PKC isoforms and serve to localize PKC to specific compartments in the cell. Among these, PKC , βII, and are translocated from the cytosol to perinuclear membrane while PKC translocates from the nucleus to myofibrils [29]. Through these RACK–PKC interactions, activated PKCs are trafficked to modulate the targets listed above via phosphorylation of serine threonine residues.

2.3 Protein kinase C and cardiac hypertrophy
Extracellular signals that elicit a response via G_q have been observed to stimulate PKC isoforms in neonatal cardiomyocytes. PKC is hypothesized to modulate cardiac hypertrophy by phosphorylation of transcription factors controlling expression of hypertrophic genes. Among these transcription factors found to be modulated by PKC in agonist stimulated cardiomyocytes are c-jun and fos [22]. Signal transduction cascades such as p42 and p44 MAPK isoforms (mitogen-activated protein kinase) that lead to c-jun and fos activation have also been found to be activated by PKC in agonist-stimulated cardiomyocytes [30]. Similar observations have been published using animal models of cardiac hypertrophy as well. Pressure overload in rats induces the translocation of PKC , βI, and βII and increases PKC-dependent phosphorylation activity [31]. Acute pathological levels of mechanical stretch of the left ventricle in the isolated adult guinea pig heart results in rapid translocation of PKC , but not other isoforms [32]. Results from our laboratory have also indicated that in the guinea pig model with constriction of the descending thoracic aorta for a period of 8 weeks, PKC and is upregulated during decompensated cardiac hypertrophy [33].

Using well-established methods of cardiac specific transgenesis, the effects of overexpressing the βII isoform of PKC have been examined in transgenic mice. Overexpression of PKC βII produces a hypertrophic phenotype, upregulation of the fetal gene program, and myocyte dysfunction, with no change in systemic blood pressure [34]. Taken together, the observations in cell culture and animal models implicate PKC isoforms as an important signal transduction pathway in the development of cardiac hypertrophy. This notion is further supported by the fact that when PKC βII overexpression mice are treated with an oral PKC βII inhibitor beginning at 3 weeks of age, the hypertrophic phenotype is largely prevented from occurring. In addition, we have recently demonstrated that inhibition of PKC translocation by an angiotensin-converting enzyme inhibition is accompanied by improved cardiomyocyte and isolated isovolumic left ventricular function during pressure overload hypertrophy and failure [33]. Though evidence is mounting for hypertrophic signaling via PKC, the fundamental question of relevance to the human condition of hypertrophy has not been addressed until recently. Examination of explanted human hearts has revealed upregulation of mRNA expression for PKC βI and βII isoforms, significant translocation of PKC , βI, βII, and an increase in PKC activity [35]. Even though there are species specific differences present in the differential PKC isoform response during cardiac hypertrophy, the activation of PKC in general is a common pathway.

	3 Conclusions

Top 1 Introduction 2 G protein-coupled receptor... 3 Conclusions References

 
Taken together these recent data from conventional animal models, genetically engineered mice and human myocardium implicate activation of the G_q, phospholipase C β, protein kinase C pathway as a major determinant of cardiac hypertrophy and heart failure. Inhibitors of this signal transduction system at multiple levels, while using established methods to reduce afterload, may provide a promising therapeutic approach to this clinically important syndrome.

Time for primary review 34 days.

	Notes

 
¹ Current address: Division of Foods and Nutrition, 250 South 1850 East #239, University of Utah, Salt Lake City, UT 84112, USA.

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Top 1 Introduction 2 G protein-coupled receptor... 3 Conclusions References

 

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