Signaling effectors underlying pathologic growth and remodeling of the heart

Cardiovascular disease is the number one cause of mortality in the Western world. The heart responds to many cardiopathological conditions with hypertrophic growth by enlarging individual myocytes to augment cardiac pump function and decrease ventricular wall tension. Initially, such cardiac hypertrophic growth is often compensatory, but as time progresses these changes become maladaptive. Cardiac hypertrophy is the strongest predictor for the development of heart failure, arrhythmia, and sudden death. Here we discuss therapeutic avenues emerging from molecular and genetic studies of cardiovascular disease in animal models. The majority of these are based on intracellular signaling pathways considered central to pathologic cardiac remodeling and hypertrophy, which then leads to heart failure. We focus our discussion on selected therapeutic targets that have more recently emerged and have a tangible translational potential given the available pharmacologic agents that could be readily evaluated in human clinical trials.

The primary function of the heart is to contract and pump blood. When contractile performance is perturbed or reduced in response to diverse (patho-)physiologic stimuli, the heart typically remodels and hypertrophies, in association with increases in myocyte cell volume (1). Pathologic hypertrophy of the myocardium temporarily preserves pump function and reduces ventricular wall stress, but prolonged cardiac hypertrophy is a leading predictor for arrhythmias and sudden death as well as dilated cardiomyopathy and heart failure (2–5). The hypertrophic growth of the myocardium is typically initiated by signal transduction pathways in response to either neuroendocrine factors or an ill-defined mechanical stretch– or wall tension–sensing apparatus (6–10). Pathologic growth of the myocardium can induce concentric remodeling of the ventricle that results in myocyte growth in a cross-sectional area, such as with hypertension or from hypertrophic cardiomyopathy due to mutations in sarcomeric genes (Figure 1). Alternatively, select pathologic stimuli, or the transition to heart failure, can also elicit an eccentric or dilatory growth response in which the chamber effectively dilates with wall thinning, most likely through a predominate lengthening of individual myocytes (Figure 1).

Figure 1

Overview of different types of cardiac hypertrophy. The normal heart can develop different types of hypertrophic remodeling depending on the stress. Exercise and pregnancy result in physiologic hypertrophy, in which individual cardiomyocytes increase in length and width and the heart undergoes a balanced type of eccentric hypertrophy (chambers, walls, and septum enlarge in unison). Pathologic stress or hypertrophic cardiomyopathy activates neuroendocrine factors that stimulate cardiac hypertrophy, often resulting in concentric remodeling, in which cardiomyocytes mostly increase in width compared with length, resulting in wall and septal thickening and a loss of chamber area. Over time, this state can deteriorate into dilated and eccentric hypertrophy, in which individual cardiomyocytes reduce in width and lengthening becomes excessive, leading to extreme chamber enlargement with loss of wall and septal thickness, along with large increases in wall tension. Some disease states can lead directly to dilated cardiomyopathy without a prior concentric remodeling phase.

In contrast to pathologic stimuli that elicit cardiac hypertrophy with poor patient prognosis, exercise and pregnancy induce a purely physiologic cardiac hypertrophy that is typically not associated with a predisposition toward future disease (11). In these cases, the myocardium grows more uniformly, with increases in chamber size, wall thickness, and myocyte length and width (Figure 1). Interestingly, Rockman and colleagues showed that the duration of the stimulus does not determine the difference between physiological and pathological hypertrophy, suggesting instead that the stimuli are inherently different (12). Accordingly, other studies have clearly shown activation of different signaling pathways in transducing either response. Physiological hypertrophy typically involves activation of IGF1/PI3K/AKT/PKB-dependent signaling, ERK1/2, or CEBPβ (13–19). These pathways or effectors have been shown to antagonize cell death in the heart or to stimulate myocyte renewal, suggesting that physiologic growth stimulation through such pathways can be cardioprotective despite causing mild heart enlargement.

Clinical management of pathologic cardiac remodeling is targeted to the underlying cause (e.g., hypertension) and typically involves a select array of pharmacologic agents that have shown efficacy in reducing hypertrophy and/or negative remodeling of the myocardium. In both humans and animal models, targeting the renin-angiotensin-aldosterone system can reverse cardiac hypertrophy or induce positive remodeling of the ventricles back to predisease states independent of effects on blood pressure, though blood pressure management is an additional protective aspect of these antagonists and is often the reason for initiating treatment (20, 21). Another highly employed agent that has antihypertrophic properties is the β-adrenergic receptor blocker (β-blocker), which can also positively influence the heart and regress negative ventricular remodeling and hypertrophy as well as extend life span in heart failure patients (21). Ca²⁺ channel blockers are also used to manage hypertension in patients, and work in animal models has suggested antihypertrophic effects of these agents that are independent of blood pressure lowering (22). All of these agents are thought to positively affect the heart and reduce hypertrophy and remodeling by limiting signaling through neuroendocrine circuitry and intracellular transduction pathways that underlie myocyte growth and are at the molecular basis of both cardiac hypertrophy and remodeling as well as heart failure (23, 24). However, additional agents are needed, as some patients are refractory to the beneficial effects of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, β-blockers, and Ca²⁺ channel blockers. Furthermore, the overall efficacy of these agents is somewhat limited, as cardiovascular disease still progresses even in responsive patients (25, 26). Here we discuss additional signaling pathways that have emerged more recently from mechanistic and genetic studies in animal models of cardiac remodeling that offer new treatment opportunities.

Inhibition of β-adrenergic receptor signaling is perhaps the most effective and frequently employed therapy in addressing negative cardiac remodeling associated with hypertension, postmyocardial infarction remodeling, or early stages of heart failure (27–30). One proposed benefit of β-receptor blockade is a myocyte-autonomous reduction in hypertrophy and cell death (31, 32). β-Adrenergic receptors are a subclass of GPCRs that elicit a number of downstream signaling events, including activation of adenylyl cyclase and elevation of cAMP as part of the acute fight-or-flight response that dramatically increases myocyte inotropy, chronotropy and lusitropy (Figure 2 and ref. 32). Increases in cAMP in the cardiomyocyte result in activation of PKA, which serves as a critical regulator of cardiac contractility by directly phosphorylating key Ca²⁺-handling proteins and contractile proteins to augment function. However, when activated for extended periods of time, such as during hypertension, heart failure, or volume overload due to valve dysfunction, these pathways may lose their initial beneficial positive chronotropic and inotropic effects (33, 34), leading to hypertrophy and β-receptor desensitization (35).

Figure 2

Signaling pathways underlying pathologic cardiac remodeling that have emerged as translational targets. Diagram of selected signaling effectors or signaling pathways that underlie cardiac hypertrophy or the transition to heart failure, with a special emphasis on immediate translational potential given the pharmacologic agents in development or clinical trials for other disorders. The diagram is also segregated into compartments in the cardiomyocyte, from receptors to second messengers to effector kinases. Some pathways lead to alterations in contractility and/or gene expression. The individual signaling mediators are discussed in the text. The diagram also depicts different therapeutic options based on known pharmacologic agents or gene therapy approaches. Green indicates drugs that are FDA approved, although not necessarily for cardiovascular indications. Red indicates treatments that are currently in phase 1 and 2 clinical trials, but again, not necessarily for cardiovascular indications. Blue indicates targets that have been identified in animal models and might be translated into phase 1 and 2 clinical trials with investigational compounds. NFAT, MEF2, and GATA4 are well-known cardiac-acting transcription factors that affect cardiovascular stress responsiveness. GPCR-BA, G-protein coupled receptor biased agonist, biased toward G-protein signaling; β-arrestin-BA, β-arrestin biased agonist. AC, adenylyl cyclase; ACE, angiotensin-converting enzyme; β-AR, β-adrenergic receptor; ARB, angiotensin receptor blocker; GC, guanylate cyclase; β-ARK-CT, β-adrenergic receptor kinase carboxyl terminus; NPR, natriuretic peptide receptor; PLC, phospholipase C; PLN, phospholamban; I-1, PP1 inhibitor 1; RYR2, ryanodine receptor 2; SERCA, sarcoplasmic reticulum Ca²⁺ ATPase. Dotted lines indicate indirect pathways.

β-Receptor desensitization and loss of dynamic and acute responsiveness may be the most detrimental effect associated with chronic receptor stimulation with augmented catecholamine load (33, 35). This process is directly regulated by GPCR receptor kinases (GRKs), some of which specifically phosphorylate the β-adrenergic receptor and modulate β-arrestin signaling, which together negatively affect the myocardium by reducing the dynamic range in β-receptor function (refs. 36, 37 and Figure 2). For example, inhibition of GRK2 in genetically modified mouse models has been shown to abate heart failure and hypertrophic remodeling while maintaining optimal contractile performance (38). These results suggest that inhibiting this pathway may have clinical applications. Indeed, viral vector–mediated overexpression of a truncated dominant-negative protein that blocks GRK2 function toward the β-receptor is advancing into phase 1 and 2 clinical trials (39). Additionally, M119, a selective GRK2 small molecule inhibitor that antagonizes G_βγ interaction with GRK2, enhances cardiomyocyte contractility in vitro and slows hypertrophy and heart failure progression in mice chronically treated with isoproterenol (Figure 2 and ref. 40).

Although various cardiac GPCRs have negative effects when stimulated chronically, β-arrestin has recently been recognized to mediate potentially beneficial downstream signaling (41). The currently available GPCR receptor blockers inhibit both G protein– and β-arrestin–mediated responses. However, select types of GPCR blockers known as biased receptor blockers can differentiate between the two components. Just such an antagonist specifically targeting the angiotensin receptor is currently being evaluated in phase 2 clinical trials (42, 43). TRV120027 inhibits the G protein–coupled response downstream of the angiotensin receptor but leaves the positive effects associated with β-arrestin signaling untouched (Figure 2). The hope is that such biased receptor inhibitors may have long-term benefits over simply blocking all downstream signaling of the receptor. Indeed, some of the existing β-receptor antagonists used in humans, such as carvedilol, function as biased agonists for β-arrestin and hence might provide additional benefit beyond simply blocking traditional coupled signaling through G_αs (44, 45).

PKCα is activated by GPCR signaling in cardiomyocytes, elicited by most neuroendocrine effectors that function through G_αq and phospholipase C activation (46). Once activated, PKCα appears to function as a nodal regulator of contractility by affecting key intracellular Ca²⁺ and myofilament contractile proteins that alter signaling and myocyte function. For example, deletion of Prkca in the mouse, which encodes PKCα, results in markedly increased basal cardiac contractility, including increased sarcoplasmic reticulum Ca²⁺ levels and Ca²⁺ cycling efficiency that protects these mice from cardiac hypertrophy and heart failure induced by cardiac stress (47, 48). Transgenic mice with dominant-negative PKCα (dn-PKCα) overexpression specific to cardiomyocytes were also protected from myocardial infarction–induced heart failure, as were diseased mice treated with PKCα/β inhibitors such as Ro-31-8220 and ruboxistaurin (Figure 2 and refs. 48–50). Ruboxistaurin treatment also reduced cardiac remodeling, fibrosis, and heart failure in rat models of heart disease and improved cardiac function in pigs after myocardial infarction (51–54). By using gene-targeted mice for Prkca, Prkcb, and Prkcg, the protective effects of ruboxistaurin were shown to result exclusively from PKCα inhibition. (55). In addition to Ca²⁺ cycling effects, ruboxistaurin may also improve contractility by inhibiting PKCα phosphorylation of myofilament proteins (56–59). Hence, inhibition of PKCα could blunt the hypertrophic response by mildly augmenting contractile function at multiple levels, thereby antagonizing the need for enhanced neuroendocrine/catecholamine drive as disease begins and progresses. Similar effects may be induced by the myosin activator omecamtiv mecarbil (which is advancing to phase 3 clinical trials to evaluate its potential as a heart failure therapy), which may also lessen cardiac hypertrophy and pathologic remodeling (60–62). However, agents like omecamtiv might increase oxygen demand and thereby have serious adverse effects when dosed too high (60–62). Ruboxistaurin has been used in well over 1,000 patients in multiple phase 2/3 clinical trials for diabetic retinopathy, with some patients treated as long as 2 years, suggesting it should be safe to use in cardiac patients as well (63–65). It is surprising that ruboxistaurin has yet to be evaluated in heart failure patients, even if just for mild inotropic support, since these agents appear safe in other human clinical trials and are overwhelmingly efficacious in animal models of heart disease (66).

In the last few years the importance of Ca²⁺/calmodulin-dependent kinase II (CaMKII) as a signaling regulator for cardiac remodeling and heart failure has become clear (67). Four genes encode the CaMKII isozymes α, β, γ, and δ, which are all activated by Ca²⁺/calmodulin and other modifications (68). For example, when short-lasting activation through Ca²⁺/calmodulin is sustained, CaMKII may become self-activated, thereby reinforcing its kinase activity (69, 70). Additionally, ROS can oxidize the kinase, which results in sustained activation (71). Like PKA and PKCα, CaMKII regulates the activity of key intracellular Ca²⁺ handling or regulatory proteins, thus affecting contractility and relaxation of the cardiomyocyte, but also affecting gene transcription by controlling nuclear shuttling of class II histone deacetylases (HDACs) (Figure 2 and refs. 67, 68). Overexpression of the CaMKIIδ isoform in the heart alters Ca²⁺ handling in several important ways and induces cardiac remodeling and disease (72, 73). Consistent with these results, mice lacking CaMKIIδ show a reduction in the cardiac hypertrophic response and/or less ventricular remodeling with cardiac pressure overload stimulation (74, 75).

Though CaMKII regulates multiple Ca²⁺-handling proteins, genetic inhibition surprisingly does not result in negative side effects in animal models. Rather, these mice are protected from arrhythmia, suggesting an additional medical application if a specific small molecule inhibitor was developed (69, 76, 77). Furthermore, Anderson and colleagues showed a link between aldosterone antagonism and inhibition of CaMKII, suggesting that the beneficial effects of aldosterone antagonism are mediated by inhibition of CaMKII (78). However, aldosterone antagonists only block aldosterone/NADPH oxidase–mediated activation of CaMKII, leaving other modes of activation unaffected. Therefore, the challenge is to directly target the kinase itself and develop a safe inhibitor that is highly specific for CaMKII. One potential candidate is SMP-114, which has been evaluated in human clinical trials for rheumatoid arthritis (Figure 2 and ref. 79). However, this CaMKII inhibitory compound has not been extensively evaluated for selectivity, nor has it been applied to animal models of heart disease.

Studies in genetically modified mice as well as pharmacological studies in animal models have suggested that inhibition of phosphodiesterase 5 (PDE5) could be a novel approach to ameliorate pathologic remodeling of the heart. PDE5 activity is dependent on cyclic GMP (cGMP) selectivity over cAMP, and enzyme inhibition with drugs such as sildenafil (Viagra) results in elevated cGMP, presumably within cardiomyocytes, which then has an antihypertrophic signaling effect (Figure 2 and ref. 80). Indeed, mice subjected to pressure overload stimulation show almost no cardiac hypertrophy when treated with sildenafil before (81, 82) and even after signs of heart failure have developed (83). Sildenafil has been evaluated in numerous human clinical trials of heart disease, including congestive heart failure, diabetic cardiomyopathy, and pulmonary hypertension, most of which showed improved endpoints and outcomes (84, 85). The molecular mechanism whereby sildenafil achieves this beneficial cardiovascular profile remains controversial, as it appears that PDE5 is not basally expressed in adult cardiomyocytes (86), and sildenafil may have some effect on PDE1 (80) and PDE3 (87) that could produce a mild increase in cAMP and an increase in inotropy (Figure 2). A mild increase in contractility might have cardioprotective effects on its own by reducing neuroendocrine drive, as discussed earlier and reviewed previously (88). An alternative mechanism for sildenafil action may be activation of PKG through an elevation in cGMP, which has been suggested to be antihypertrophic by signaling to downstream effectors such as calcineurin–nuclear factor of activated T cells (Cn-NFAT), regulator of G protein signaling, and transient receptor potential canonical 6 (TRPC6), as well as the RhoA-Rho kinase pathway, which by itself may be a potential therapeutic target against pathologic cardiac remodeling, especially since specific pharmacologic agents are already used in animal models as well as human patients (81, 82, 85, 89–93). Regardless of the downstream mechanisms, studies to date in animal models suggest that sildenafil, and possibly tadalafil and vardenafil, might be therapeutically efficacious in the treatment of pathologic cardiac remodeling prior to or coincident with the onset of heart failure, as results from early clinical trials already suggest some efficacy in patients with more advanced heart failure and/or right heart disease due to pulmonary arterial hypertension (Figure 2).

The MAPK signaling cascade is classically initiated by activation of small G proteins in cardiomyocytes, followed by activation of successively acting protein kinases composed of three to five levels of phosphorylation-based amplification signaling (Figure 2). The MAPK cascade is subdivided into three main branches consisting of p38 kinases, JNKs, and ERK1/2. Additional side branches in this cascade include ERK5 and its upstream activator MEK5, as well as ERK3/4, although the upstream regulatory kinases for these effectors are not well characterized (94, 95). The JNKs and p38 kinases, which are activated by MEK4/7 and MEK3/6, respectively, generally serve as more specialized transducers of stress or injury responses, hence their classification as stress-activated protein kinases, while ERK1 and ERK2, which are activated by MEK1/2, are more specialized for mitogenic and growth factor transduction events and associated cellular processes.

Nearly all MAPK signaling components (upstream and downstream) are activated in end-stage human heart failure as well as in animal models of pathologic cardiac hypertrophy (96–98). Since this topic has been extensively reviewed previously (95), here we will only highlight the most medically relevant results that suggest therapeutic options. Constitutive activation of ERK1/2 signaling in the heart through expression of activated MEK1 produces concentric cardiac hypertrophy with thickening of individual myocytes, although it does not progress to failure and is protective against cell death (99, 100). Moreover, genetic inhibition of ERK1/2 signaling in the heart with either constitutive expression of an ERK1/2-specific dual-specificity phosphatase or by combinatorial deletion of Erk1 and Erk2 promotes cardiac dilation by enhancing growth in myocyte length (101–103). Thus, inhibition of MEK1/2 or ERK1/2 in patients with severe concentric remodeling and restrictive cardiomyopathy might be a therapeutic option. A number of different MEK1 inhibitors, such as PD-0325901, are being used in human clinical trials for cancer, all of which show safety and some of which have good oral bioavailability (Figure 2 and ref. 104).

Overexpression of MKK6 (p38 activation), MKK7 (JNK activation), or MEK5 (ERK5 activation) in the hearts of transgenic mice have each suggested a disease-causing effect of these kinases (105–107). Each appears to induce extreme cardiac dilation and decompensation with loss of contractile function, suggesting that inhibiting JNK, p38, or ERK5 with an appropriate pharmacologic agent might be therapeutic and antagonize the transition to dilated heart failure (Figure 2 and refs. 95, 108). However, cardiac-specific deletion of the gene encoding p38α predisposes mice to disease with worse cardiac function, and dn-p38α mice develop more cardiac hypertrophy with pressure overload stimulation (109, 110). Similarly, transgenic mice expressing dn-JNK1/2 in the heart as well as combinatorial deletion of the 3 and 4 alleles of Jnk1 and Jnk2 (deletion of all 4 allele result in embryonic lethality) produced more hypertrophy with pressure overload stimulation (111). Mice lacking cardiac MKK4 or MKK7 are also more prone to heart disease with pressure overload stimulation, suggesting a protective function for these pathways in addition to the previously described maladaptive aspects of their signaling (112, 113). Thus pharmacologic inhibition of JNK or p38 as a treatment for human heart disease would be more complicated if these animal studies directly translate (Figure 2). However, hamsters with muscular dystrophy and associated heart disease show less fibrosis and better cardiac function with systemic p38 MAPK inhibitor treatment, though a JNK inhibitor has no effect (114). Similar cardioprotection has also been observed in diabetic mice treated with a p38 MAPK inhibitor (115) and in mice following myocardial infarction injury (116). Therefore, pharmacological inhibition of p38 (or MKK6) and JNK (or MKK4/7) might have value to inhibit fibrosis or for select types of cardiac disease such as diabetic cardiomyopathy.

In addition to the terminal MAPK effectors and their upstream MAPKKs, the MAPKKKs have been suggested as important regulators of cardiac hypertrophy and/or transition to dilation. A number of these MAPKKKs modulate cardiac hypertrophy and heart failure, such as TAK1, PAK1, ASK1, and MEKK1 (117–123). However, these are less tangible targets since there are currently no drugs available with high specificity toward any of these. Indeed, the ability to achieve appropriate specificity toward just one individual kinase within a backdrop of some 500 serine-threonine kinases is a unique challenge for drug development, as even current investigational compounds that have been highly refined only achieve “fingerprints” of varying selectivity. Despite this note of caution, the translation of many of the kinase-inhibitory drugs into the cardiac disease realm is still potentially important toward the goal of achieving greater efficacy and life span extension than the current standard of care agents offer.

HDACs remove acetyl groups from lysine residues in target proteins and are key regulators of epigenetics through their activity toward histones in chromatin (124). Hence inhibition of HDACs might represent a novel therapeutic vantage point for pathologic cardiac hypertrophy/remodeling, given the known profile of gene expression changes that are commensurate with the disease (Figure 2). Genetically, mice lacking Hdac9 or Hdac5 genes show spontaneous cardiac hypertrophy with aging or exaggerated pathologic hypertrophy with pressure overload stimulation, suggesting that select class IIa HDACs are normally suppressors of disease (125). Thus, a pharmacologic compound that selectively inhibits class IIa HDACs would likely be deleterious. Indeed, a pharmacologic compound that selectively inhibits class IIa HDAC binding with MEF2 has been shown to impair myogenesis, which could be deleterious to cardiac function (126).

A more relevant therapeutic target are the class I HDACs, for which a number of clinical-grade pharmaceuticals have been developed (127). Indeed, pan-HDAC inhibitors reduce cardiac hypertrophy due to pressure overload stimulation, angiotensin II infusion, or isoproterenol in rodent models (128–130). This effect may be more specific to HDAC1, -2, or -3, as the more selective class I HDAC inhibitor apicidin suppresses cardiac hypertrophy and improves function in a mouse model of pressure overload (131). HDAC inhibitors also reduce fibrosis and negative remodeling of the heart after myocardial infarction injury in the rat, as well as in rat models of spontaneous and salt-sensitive hypertension (132–134). These results are consistent with genetic studies in Hdac2-null mice, which show less cardiac hypertrophy induced by various pathologic stimuli (135). However, conflicting results from another group that created heart-specific Hdac1- or Hdac2-null mice showed no attenuation of the hypertrophic response by either gene deletion following pressure overload stimulation or isoproterenol infusion (136). Thus, the genetics remain complicated by redundancy in this gene family, although pharmacologic studies in animal models of hypertrophy consistently support a therapeutic effect (Figure 2). The HDAC inhibitor romidepsin is FDA approved for the treatment of cutaneous T cell lymphoma, but arrhythmia and low white blood cell counts have been noted as significant concerns with this agent (137, 138). Although another FDA-approved HDAC inhibitor, vorinostat, has not shown such complications at this point, caution is warranted for its use in hypertrophy or heart failure because potential side effects cannot be ruled out at this point (139, 140).

Ca²⁺ channel blockers used for hypertension are also effective in reducing cardiac hypertrophy. While these drugs lower blood pressure, they have not shown benefit in heart failure and are generally avoided because of the potential risk of arrhythmias and negative inotropic effects (141). Recent evidence in genetically modified mice with cardiac-specific loss of the L-type Ca²⁺ channel, which is the primary mechanism for Ca²⁺ entry in a cardiomyocyte, showed that reduced activity of these channels leads to a compensatory leak from the ryanodine receptor and induction of cardiac hypertrophy (142). Thus, Ca²⁺ channel blockers might not be a straightforward therapeutic option for other forms of heart disease that are independent of hypertension. Additional coverage of alterations in Ca²⁺ handling through ryanodine receptor 2, sarcoplasmic reticulum Ca²⁺ ATPase, and phospholamban in heart failure are directly discussed in this Review series (Figure 2 and ref. 143).

Another potential cutting-edge therapeutic angle that affects Ca²⁺ signaling and pathologic hypertrophy is the inhibition of TRPC channels (Figure 2). TRPC channels permeate Ca²⁺ and Na⁺ in specific microdomains to initiate and/or maintain cardiac hypertrophy in association with GPCR signaling, which generates diacylglycerol to activate these channels (144, 145). Studies in mice have suggested that increased activity of either TRPC3 or TRPC6 in the heart, both of which are normally induced with hypertrophy, is sufficient to cause ventricular remodeling, dilation, hypertrophy, and disease (146, 147). Cardiac-specific expression of dn-TRPC3, dn-TRPC4, or dn-TRPC6 each antagonized the degree of cardiac hypertrophy after pressure overload stimulation or infusion of phenylephrine/angiotensin II (148). Similarly, mice deficient in Trpc1 showed reduced cardiac hypertrophy and disease after pressure overload or neuroendocrine agonist stimulation (149). These results suggest that an appropriately designed inhibitor that blocks one or more of these TRPC channels might be an effective therapeutic for cardiac hypertrophy or the transition to heart failure. Indeed, the presumed TRPC3/6 selective inhibitor Pyr3 was shown to attenuate pressure overload cardiac hypertrophy in mice (150). Thus, TRPC channels might represent novel targets for cardiac hypertrophy and failure, especially given the numerous compounds emerging from the pharmaceutical industry with specificity for the TRPM and TRPV subfamilies (151).

An important downstream effector that mediates the pro-hypertrophic effects of TRPC channels in the heart is the Cn-NFAT signaling circuit. Cn is a Ca²⁺-activated serine-threonine protein phosphatase that dephosphorylates NFAT in the cytoplasm, resulting in its nuclear translocation and activation of hypertrophic gene expression (Figure 2). Nearly 15 years ago, Cn-NFAT signaling was proposed to be both necessary and sufficient for cardiac hypertrophy (152, 153). Since then, a large number of genetic studies in the mouse and pharmacologic-based studies in mice and rats have proven the absolute centrality of this Ca²⁺-activated signaling circuit in mediating cardiac hypertrophy (154, 155), suggesting that Cn inhibitors could be used to treat associated cardiac disease states. However, the immunosuppressive effects of Cn inhibitors, together with other more severe side effects associated with the higher dosages that are needed to treat hypertrophy, likely preclude such an approach in humans.

Although other potential targets exist, such as metabolism and redox regulation, mTOR inhibition by rapamycin, or even treatment with peptides such as adiponectin, the pathways discussed here fit a central theme of emerging inibitors that affect signaling pathways (156, 157). Indeed, the current standard-of-care pharmacologic agents that are used to treat hypertension and heart failure also reduce cardiac hypertrophy by targeting signaling effectors. Despite these current agents, the incidence and prevalence of heart failure is still increasing, underscoring the need for agents that act earlier or are more effective (26, 158, 159). Because many of the targets highlighted here have existing or newly developed pharmacologic agents with reasonable specificity and safety, the hope is that additional clinical trials can be instituted quickly for patients in early-stage heart failure, patients with hypertrophy that is nonresponsive to the standard-of-care agents, or in patients with hypertrophic cardiomyopathy due to mutations in sarcomeric genes. While presentation of cardiac hypertrophy is not typically an endpoint in clinical trials, diastolic dysfunction and early-stage heart failure might be. Many of the signaling pathways and effectors that induce pathologic hypertrophy in the first place likely lead to diastolic dysfunction and heart failure, so many of the pathways outlined here might be effective early and late in the disease process that culminates in heart failure. Therefore, as the use of animal models continues to uncover additional signaling effectors of cardiac hypertrophy and heart failure, agents against these targets might be translated into clinical trials to maintain a seamless pipeline of therapeutic options until a more efficacious treatment is uncovered.

This work was supported by an American Heart Association postdoctoral fellowship (to J.H. van Berlo) and by grants from the NIH (to J.D. Molkentin and M. Maillet) and the Howard Hughes Medical Institute (to J.D. Molkentin).

Address correspondence to: Jeffery D. Molkentin, Howard Hughes Medical Institute, Division of Molecular Cardiovascular Biology, Cincinnati Children’s Hospital Medical Center, 240 Albert Sabin Way, MLC 7020, Cincinnati, Ohio 45229-3039, USA. Phone: 513.636.3557; Fax: 513.535.5958; E-mail: Jeff.molkentin@cchmc.org.

Conflict of interest: The authors have declared that no conflict of interest exists.

Reference information: J Clin Invest. 2013;123(1):37–45. doi:10.1172/JCI62839.

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