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• W2002806885 abstract "The study of complex heart diseases has always been a vexing task, akin to solving a 1000-part jigsaw puzzle with few obvious connecting pieces. Acquired cardiovascular diseases, such as atherogenesis and heart failure, arise via the interaction of environmental factors and genetic susceptibility to produce complicated lesions that cannot be explained by a single gene or pathway. Distinguishing primary from secondary events, proving causality, and finding the intersecting pieces has proven a significant challenge. Nevertheless, as evidenced by the pioneering work on the LDL receptor pathway in atherogenesis, genetic-based analysis of relatively rare diseases that exhibit the clinical cardiovascular phenotype of interest can yield mechanistic insight into complex heart diseases (3Brown M.S Goldstein J.L Cell. 1997; 89: 331-340Abstract Full Text Full Text PDF PubMed Scopus (2797) Google Scholar). Often, this requires not only identifying the disease gene, but eventually connecting the gene to molecular pathways that initiate, promote, suppress, and potentially reverse surrogate endpoints of the disease phenotype. Ironically, the dramatic improvement in survival from acute coronary disease has led to an increase in heart failure of epidemic proportions, which now is the leading cause of combined morbidity and mortality in the US and other developed nations. Unfortunately, our understanding of the molecular pathways leading to heart failure is primitive, and the “cholesterol,” i.e., key risk factor, that drives the underlying disease process is unknown. However, a flurry of recent papers describing rare monogenic forms of human dilated cardiomyopathy and gene-targeted mouse models of muscle-specific mutations have allowed the identification of genetic pathways that can lead to dilated cardiomyopathy, a major form of human heart failure characterized by a progressive, uniform dysfunction of the entire myocardium. Since dilated cardiomyopathy can occur independently of coronary artery disease, and often has a genetic component, analysis of this subset of heart failure provides an opportunity to uncover intrinsic muscle-specific pathways for heart failure. This minireview will highlight these pieces of the dilated cardiomyopathy puzzle that may serve as a paradigm for acquired forms of heart failure. Biomechanical stress resulting from hypoxia, hypertension, and other forms of myocardial injury is the first cornerstone of any proposed model of dilated cardiomyopathy. The loss of functional myocardium creates additional biomechanical stress on the remaining viable heart muscle, thereby triggering signals for a compensatory increase in cardiac muscle mass, known as hypertrophy (reviewed by 5Chien, K.R., Grace, A.A., and Hunter, J.J. (1999). In The Molecular Basis of Cardiovascular Disease, K.R. Chien, ed. (Philadelphia: W.B. Saunders Company), pp. 211–250.Google Scholar). A transition can occur whereby an irreversible decompensation in cardiac function occurs during the dilation of the heart and thinning of the walls of the ventricular chamber (Figure 1). Familial hypertrophic cardiomyopathy, which at first is not accompanied by chamber dilation, occurs due to mutations affecting proteins in the sarcomere, which comprises the contractile machinery of heart muscle (18Seidman, C.E., and Seidman, J.G. (1999). In The Molecular Basis of Cardiovascular Disease, K.R. Chien, ed. (Philadelphia: W.B. Saunders Company), pp. 251–263.Google Scholar), while familial dilated cardiomyopathy has now been linked to mutations in cytoskeletal genes (for a list, see 4Chen J Chien K.R J. Clin. Invest. 1999; 103: 1483-1485Crossref PubMed Scopus (67) Google Scholar). In addition, mice harboring muscle-specific mutations in extra-sarcomeric cytoskeletal proteins display a dilated cardiomyopathy phenotype, consistent with a direct role of the cytoskeleton in intrinsic signals for dilated cardiomyopathy. Accordingly, it is now critical to show whether these cytoskeletal proteins have a nonspecific structural role or a specific signaling role in chamber dilation. The first genetic link between the cytoskeleton and cardiomyopathy was provided by the discovery that mutations in dystrophin or its associated proteins can cause familial forms of dilated cardiomyopathy and skeletal myopathies (Figure 2). Duchenne and Becker muscular dystrophy, two of the most common genetic neuromuscular diseases, are caused by a variety of mutations in the dystrophin gene. The sarcoglycan proteins are a subcomplex of transmembrane proteins within the dystrophin–glycoprotein complex (DGC) (reviewed by 7Hemler M.E Cell. 1999; 97: 543-546Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar). Mutation of sarcoglycan genes results in limb girdle muscular dystrophies (LGMDs), and these patients often present with associated cardiomyopathy. Mutations in a single sarcoglycan subunit result in reduction or absence of the sarcoglycan complex in skeletal muscle. Until recently, it has been assumed that the muscle phenotypes in LGMD patients reflect the intrinsic loss of the sarcoglycan complex in skeletal or cardiac muscle. In the previous issue of Cell, Kevin Campbell and colleagues suggest a novel pathway for the pathogenesis of cardiomyopathy and muscular dystrophy (6Coral-Vazquez R Cohn R.D Moore S.A Hill J.A Weiss R.M Davisson R.L Straub V Barresi R Bansal D Hrstka R.F Williamson R Campbell K.P Cell. 1999; 98: 465-474Abstract Full Text Full Text PDF PubMed Scopus (312) Google Scholar). The phenotypes of mice lacking α or δ sarcoglycan suggest that disruption of the sarcoglycan subcomplex in vascular smooth muscle is of paramount importance. The expression of α and γ subunits is restricted to skeletal and cardiac muscle, whereas β, δ, and ε subunits are also expressed in other tissues. Mice lacking the α or δ subunit have no detectable sarcoglycan complex in both skeletal muscle and heart. However, the two mouse models differ in their phenotypic presentation. Both types of mice develop skeletal muscle dystrophy, yet only the δ knockout mice exhibit cardiomyopathy. In keeping with the expression profile of each subunit, the δ, but not the α, knockout mice exhibit a substantial loss of the sarcoglycan complex in vascular smooth muscle. This loss is associated with vascular malfunction and irregularities of coronary artery vasculature. The demonstration that vascular defects may be a pivotal factor in the development of some cardiomyopathies opens the door to novel therapeutic targets. Microvascular dysfunction associated with focal myocardial necrosis had been described previously in a hamster model, BI014.6, of hypertrophic cardiomyopathy that has subsequently been shown to be the result of a 5′ deletion of the δ-sarcoglycan gene (see 6Coral-Vazquez R Cohn R.D Moore S.A Hill J.A Weiss R.M Davisson R.L Straub V Barresi R Bansal D Hrstka R.F Williamson R Campbell K.P Cell. 1999; 98: 465-474Abstract Full Text Full Text PDF PubMed Scopus (312) Google Scholar, and references therein). It will be of interest to reexamine this hamster model in light of the Campbell group's findings. Interestingly a strain derived from BIO14.6, TO-2, carries the same deletion but exhibits dilated, rather than hypertrophic cardiomyopathy. This clearly demonstrates that another genetic modifier gene(s) is involved in the manifestations of cardiomyopathy. Despite this exciting new finding, it is clear that not all cardiomyopathies associated with sarcoglycan deficiency can be attributed to vascular smooth muscle involvement. Mice lacking the γ subunit which, like α, is selectively expressed in striated muscle, also evidence a reduction in the sarcoglycan complex in both skeletal and cardiac muscle. However, in contrast to the α knockout, γ knockout mice display both muscular dystrophy and cardiomyopathy. This discrepancy remains to be explained. There is also a potential interaction between muscular dystrophy and cardiomyopathy, which remains to be clarified. Mouse mdx mutants carry a mutation in the dystrophin gene, and exhibit mild muscular dystrophy, but no cardiomyopathy, despite the disappearance of the dystrophin–glycoprotein complex in cardiac and skeletal muscle. Mouse mdx mutants that also carry a mutation in MyoD, a skeletal muscle specific transcription factor, have a much more severe muscular dystrophy, due to the inability of the double mutant to replenish damaged muscle by satellite cell-mediated regeneration (13Megeney L.A Kablar B Perry R.L Ying C May L Rudnicki M.A Proc. Natl. Acad. Sci. USA. 1999; 96: 220-225Crossref PubMed Scopus (97) Google Scholar). Although MyoD is skeletal muscle specific, the doubly mutant mice develop cardiomyopathy. Disruption of the dystrophin–glycoprotein complex in heart may engender the development of cardiomyopathy via a secondary response to a physiological stimulus of volume overload. Recent studies of mice lacking a muscle-specific LIM domain protein (MLP) provide further support for an intrinsic role for cardiomyocyte cytoskeletal proteins in chamber dilation (1Arber S Hunter J.J Ross Jr., J Hongo M Sansig G Borg J Perriard J.-C Chien K.R Caroni P Cell. 1997; 88: 393-403Abstract Full Text Full Text PDF PubMed Scopus (677) Google Scholar). MLP is localized in the actin-based cytoskeleton in individual cardiac muscle cells (Figure 2). Mice lacking MLP display a severe form of dilated cardiomyopathy with many features of the human disease. MLP contains two LIM domains that likely serve as protein–protein interaction modules that link MLP with other cytoskeletal components. A nuclear localization signal is found between the two LIM domains, and MLP is located in the nucleus. Interestingly, MLP is a transcriptional coactivator for MyoD, and has previously been reported to be involved in the myoblast-myotube transition (11Kong Y Flick M.J Kudla A.J Konieczny S.F Mol. Cell. Biol. 1997; 17: 4750-4760Crossref PubMed Scopus (230) Google Scholar). Intriguingly, MLP may regulate cardiac muscle cell transcription in a manner similar to that found for cytoskeletal actin with regards to SRF activation (20Sotiropoulos A Gineitis D Copeland J Treisman R Cell. 1999; 98: 159-169Abstract Full Text Full Text PDF PubMed Scopus (562) Google Scholar). Since over 30% of idiopathic cardiomyopathies are suspected of having a familial component, utilizing publicly available databases to find sequence variants of cytoskeletal genes that confer a risk for dilated cardiomyopathy could also be of value. This approach has already resulted in the identification of a sequence variant in the cytoskeletal domain of cardiac actin as a disease gene in a subset of patients with dilated cardiomyopathy (15Olson T.M Michaels V.V Thibodeau S.N Tai Y.S Keating M.T Science. 1998; 280: 750-752Crossref PubMed Scopus (564) Google Scholar). The recent identification of a mutation in a nuclear intermediate filament, lamin A, in a subset of human dilated cardiomyopathies (2Bonne G DiBarletta M.R Varnous S Baecane H.M Hammouda E.H Merlini L Muntoni F Greenberg C.R Gary R Urtizberea J.A et al.Nat. Genet. 1999; 21: 285-288Crossref PubMed Scopus (1039) Google Scholar), suggests that mutations throughout the cytoskeletal network might be linked to chamber dilation (Figure 2). The loss of functional myocytes can trigger the onset of acute heart failure in cases of myocardial infarction. The loss of cardiac myocytes via cell death pathways may also play an important role in the progression of the chronic course to dilated cardiomyopathy. Apoptosis can occur during cardiac hypertrophy and failure, and the increased release of tumor necrosis factor (TNF) and other proapoptotic cytokines in the postischemic myocardium has been reported. As revealed by cultured myocyte and transgenic animal studies, the overexpression of signaling proteins, such as Gq and p38 MAP kinases, can trigger a hypertrophic response and lead to cardiomyocyte apoptosis (5Chien, K.R., Grace, A.A., and Hunter, J.J. (1999). In The Molecular Basis of Cardiovascular Disease, K.R. Chien, ed. (Philadelphia: W.B. Saunders Company), pp. 211–250.Google Scholar, and references therein). The recent discovery of myocyte survival pathways has provided the strongest evidence to date that the loss of functional myocytes may drive the onset of chamber dilation in response to biomechanical stress (8Hirota H Chen J Betz U.A.K Rajewsky K Gu Y Ross Jr., J Mueller W Chien K.R Cell. 1999; 97: 189-198Abstract Full Text Full Text PDF PubMed Scopus (567) Google Scholar and references therein). In 1995, cardiotrophin-1 (CT-1), a member of the IL-6 cytokine family, was identified by expression cloning using an in vitro model of cardiogenesis in mouse embryonic stem cells. CT-1 is one of the most potent cardiac myocyte survival factors thus far described, and acts via gp130/leukemia inhibitory factor receptor β heterodimer pathways to block myocyte apoptosis. Mice that harbor a ventricular restricted knockout of gp130 have a normal basal cardiac phenotype, but display rapid onset dilated cardiomyopathy and massive myocyte apoptosis following biomechanical stress. Thus, biomechanical stress concomitantly activates hypertrophic and apoptotic programs, as evidenced by the shared components in their downstream signaling pathways. At the same time, the stress-activation of gp130-dependent myocyte survival pathways tilts the balance in favor of hypertrophy, allowing the onset of a compensatory response versus chamber dilation. The identification of the downstream targets of this myocyte survival pathway will allow a rigorous test of this model, in which hypertrophy per se is viewed as compensatory, and the transition to heart failure occurs via the constitutive activation of proapoptotic signals (Figure 3). The immediate clinical relevance of myocyte survival pathways has been revealed by surprising observations in patients receiving ErbB2 receptor antibodies (Herceptin) as adjunctive therapy for breast cancer (19Slamon D Leyland-Jones B Shak S Paton V Bajamonde A Fleming T Eiermann W Wolter J Baselga J Norton L Proc. Am. Soc. Clin. Oncol. 1998; 17: 98aGoogle Scholar). A large-scale clinical trial has documented the efficacy of Herceptin as an adjunctive therapy for metastatic breast cancer, but uncovered the onset of clinical heart failure in 15% of the patients receiving the drug. The clinical phenotype resembles the rapid onset of dilated cardiomyopathy seen in the gp130 mutant mice. Patients with previous exposure to anthracyclines, are at the highest risk, suggesting a combinatorial effect. Neuregulin, a secreted peptide found in cardiac endothelium, can directly promote in vitro cardiac myocyte survival via ErbB2–ErbB4 heterodimer pathways (5Chien, K.R., Grace, A.A., and Hunter, J.J. (1999). In The Molecular Basis of Cardiovascular Disease, K.R. Chien, ed. (Philadelphia: W.B. Saunders Company), pp. 211–250.Google Scholar and references therein), and mutation of ErbB2 and ErbB4 leads to cardiac myocyte apoptosis and an embryonic form of cardiomyopathy (reviewed by 12Marchionni M.A Nature. 1995; 378: 334-335Crossref PubMed Scopus (58) Google Scholar). Taken together, these results suggest that neuregulin-dependent pathways may play an important role in basal myocyte survival. The recent discovery of gp130–ErbB2 heterodimeric receptors (16Qiu Y Ravi L Kung H.J Nature. 1998; 393: 83-85Crossref PubMed Scopus (263) Google Scholar) suggests the fascinating possibility of an unknown ligand for cardiac myocyte survival (Figure 3). The physiological hallmark of all forms of end-stage heart failure is the severe loss of cardiac contractile function. In this regard, decreases in peak calcium transients have recently been shown to be a feature of end-stage human dilated cardiomyopathy. Since calcium is the currency of cardiac contractility, the potential role of calcium regulatory proteins has been of particular mechanistic interest. The difficulty has been to distinguish between primary events that drive the progressive decline in contractile function versus secondary physiological events. The analysis of genetically engineered animals has revealed a significant role for sarcoplasmic reticulum calcium cycling as another piece of the dilated cardiomyopathy puzzle. In the normal heart, the action of the sarcoplasmic reticulum (SR) calcium ATPase pump (SERCA 2) results in the sequestration of calcium in SR, leading to cardiac relaxation (Figure 2). The consequent increase in SR calcium stores leads to an increase in the quantal release of calcium by ryanodine receptors, the calcium release channels embedded in the SR. In this manner, increases in SERCA activity can increase both cardiac relaxation and contractility. SERCA 2 activity is regulated by its direct interaction with phospholamban, an endogenous muscle-specific inhibitor of this calcium pump (9Kadambi V.J Kranias E.G J. Cardiac Failure. 1998; 4: 349-361Abstract Full Text PDF PubMed Scopus (14) Google Scholar, and references therein) that is itself regulated by phosphorylation via the β-adrenergic receptor/Gs/cAMP pathway (10Koch W.J Rockman H.A Samma P Hamilton R.A Bond R.A Milano C.A Lefkowitz R.J Science. 1995; 268: 1350-1353Crossref PubMed Scopus (616) Google Scholar, and references therein). cAMP activation of PKA leads to the phosphorylation of phospholamban, thereby relieving its inhibition of SERCA 2. Intriguingly, mice lacking phospholamban display an augmentation of both cardiac contractility and relaxation, without any long-term pathological effects (9Kadambi V.J Kranias E.G J. Cardiac Failure. 1998; 4: 349-361Abstract Full Text PDF PubMed Scopus (14) Google Scholar). In addition, overexpression of a peptide inhibitor of the β-adrenergic receptor kinase (10Koch W.J Rockman H.A Samma P Hamilton R.A Bond R.A Milano C.A Lefkowitz R.J Science. 1995; 268: 1350-1353Crossref PubMed Scopus (616) Google Scholar) can rescue the heart failure phenotype of MLP-deficient mice with dilated cardiomyopathy (17Rockman H.A Chien K.R Choi D.-J Iaccarino G Hunter J.J Ross Jr., J Lefkowitz R.J Koch W.J Proc. Natl. Acad. Sci. USA. 1998; 95: 7000-7005Crossref PubMed Scopus (418) Google Scholar). Since phospholamban is regulated by the β-adrenergic pathway, SR calcium cycling defects provide a potential molecular mechanism for the progressive decrease in cardiac contractility and relaxation in dilated cardiomyopathy. A calcineurin-dependent pathway can regulate the fetal gene program during hypertrophy (14Molkentin J.D Lu J.F Antos C.L Markham B Richardson J Robbins J Grant S.R Olson E.N Cell. 1998; 93: 215-228Abstract Full Text Full Text PDF PubMed Scopus (2138) Google Scholar), supporting a direct role of calcium as a signal for specific phenotypic features of dilated cardiomyopathy. Accordingly, establishing genetic-based screens for known and novel coregulators of SR calcium content in heart muscle cells could be of value. Stress-related pathways can be linked to each of these four pieces of the dilated cardiomyopathy puzzle: biomechanical stimuli, cytoskeletal signaling, myocyte survival, and SR calcium cycling. While the “cholesterol” of dilated cardiomyopathy has yet to be identified, genetic clustering suggests the likelihood that chronic increases in wall stress mediated via cytoskeletal pathways may lead to the concomitant activation of downstream effects on myocyte survival, apoptosis, hypertrophy, and calcium cycling that drive the progression of heart failure. If such is the case, it may become possible to reverse the process of dilated cardiomyopathy by relieving wall stress at the molecular level. Given the pace and quality of recent work from many laboratories, the solution to the puzzle of heart failure may be closer than previously imagined." @default.
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• W2002806885 title "Stress Pathways and Heart Failure" @default.
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