A Case for Adaptive Cardiac Hypertrophic Remodeling Is CITED
2020; Lippincott Williams & Wilkins; Volume: 127; Issue: 5 Linguagem: Inglês
10.1161/circresaha.120.317623
ISSN1524-4571
AutoresTomoya Sakamoto, Daniel P. Kelly,
Tópico(s)Cardiovascular Function and Risk Factors
ResumoHomeCirculation ResearchVol. 127, No. 5A Case for Adaptive Cardiac Hypertrophic Remodeling Is CITED Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBA Case for Adaptive Cardiac Hypertrophic Remodeling Is CITED Tomoya Sakamoto and Daniel P. Kelly Tomoya SakamotoTomoya Sakamoto Department of Medicine, Cardiovascular Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia. and Daniel P. KellyDaniel P. Kelly Correspondence to: Daniel P. Kelly, MD, Perelman School of Medicine, University of Pennsylvania 3400 Civic Center Blvd, Bldg 421, Smilow Translational Research Center, Room 11-122 Philadelphia, PA 19104. Email E-mail Address: [email protected] https://orcid.org/0000-0002-3811-9491 Department of Medicine, Cardiovascular Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia. Originally published13 Aug 2020https://doi.org/10.1161/CIRCRESAHA.120.317623Circulation Research. 2020;127:647–650This article is a commentary on the followingCITED4 Protects Against Adverse Remodeling in Response to Physiological and Pathological StressArticle, see p 631The postnatal heart responds to chronic hemodynamic stress by mounting a hypertrophic growth response. Two general types of cardiac hypertrophy have been described: physiological and pathological.1 Physiological hypertrophic growth occurs during postnatal development and in response to chronic intermittent changes in workload that occur, for example, with endurance exercise training. Physiological hypertrophy is considered adaptive with commensurate and highly orchestrated augmentation of myofilaments and mitochondrial ATP-producing capacity. Pathological forms of cardiac hypertrophy occur in the context of chronic persistent pressure or volume overload and in a subset of genetic cardiomyopathies. In contrast to physiological forms of cardiac hypertrophy, pathological forms of hypertrophic growth trigger distinct changes in contractile and energy metabolic programs that are reminiscent of the fetal heart and often progress to a decompensated adversely remodeled state including cardiac fibrosis, myocyte death, and ventricular dilatation leading to heart failure. Current dogma, based in part on observations in which pathological cardiac hypertrophic growth has been genetically or pharmacologically inhibited in mouse models,2,3 is that pathological hypertrophic growth is maladaptive and contributes to the pathogenesis of heart failure.Significant progress has been made in the identification of cellular signaling and gene regulatory events involved in pathological cardiac hypertrophic growth including activation of calmodulin-dependent protein kinase/calcineurin signaling and a transcriptional regulatory circuit that involves myocyte enhancer factor-2, nuclear factor of activated T-cells, and histone deacetylases4–6 among other factors. However, much less is known about the molecular drivers of physiological growth. Insight into the latter could unveil new therapeutic strategies for promoting adaptive growth in chronic pathophysiological states that lead to heart failure. An important breakthrough in the identification of putative upstream drivers of physiological cardiac hypertrophy was unveiled in a genome-wide screen of transcriptional regulators in a mouse model of exercise-induced cardiac hypertrophy.7 This screen identified CITED4 (CBP [CREB-binding protein]/p300-interacting transactivators with E [glutamic acid]/D [aspartic acid]-rich-carboxyterminal domain) as a cardiac myocyte-enriched factor that was induced in heart with exercise. CITED4 is a non-DNA binding transcriptional regulator that is believed to function with transcription factors, such as CBP/p300.7 Cardiac-specific overexpression of CITED4 in mice was shown to promote physiological cardiac hypertrophy and enhance functional recovery after ischemia/reperfusion injury.8 These results demonstrated that CITED4 is capable of driving adaptive cardiac hypertrophy, but its role as an endogenous regulator was not defined. In this issue of Circulation Research, Lerchenmuller et al9 investigated the potential role of CITED4 as a necessary regulator of adaptive cardiac hypertrophy by developing cardiac myocyte specific CITED4 knockout (C4KO) mice. The cardiac phenotype of C4KO mice was normal at baseline, but interesting changes were observed in conditions of chronic physiological (swimming exercise) or pathological (transverse aortic banding, TAC [transverse aortic banding]) stress. Swimming training resulted in mild ventricular dysfunction and reduced cardiomyocyte size in the C4KO mice compared with trained controls, indicative of a defect in the adaptive hypertrophic response. Interestingly, the C4KO mice also exhibited severe pathological remodeling compared with controls in response to TAC, including ventricular wall thinning and cavity dilatation along with severely reduced left ventricular function. On a cellular level, the C4KO hearts exhibited severe fibrosis and evidence for increased autophagy. These results indicated that CITED4 is not only necessary for adaptive cardiac hypertrophy but also defends against chronic pathological stress. The latter finding suggested that some components of the pathological hypertrophic response may be adaptive.To delineate the protective responses downstream of CITED4 observed in the TAC studies, Lerchenmuller et al9 focused on candidate pathways. Their previous work indicated that the protection afforded by CITED4 to cardiac ischemia/reperfusion injury involved activation of mTOR (mammalian target of rapamycin) signaling. Indeed, they found that the distal limb of mTOR signaling was diminished in the C4KO mice one week after TAC surgery and that this is due, at least in part, to activation of known tuberous sclerosis–dependent mTORC1 suppressors, REDD1 (regulated in development and DNA damage response 1, also known as DDIT4 [DNA damage inducible transcript 4]) and REDD2 (regulated in development and DNA damage response 2, also known as DDIT4L [DNA damage-inducible transcript 4-like protein]). These results suggest that CITED4-mediated activation of mTOR signaling serves to promote potentially adaptive responses, such as cardiac myocyte growth and inhibition of autophagy, and that this occurs relatively early after the onset of pressure overload.Whole-genome profiling of the C4KO hearts post-TAC also provided a clue regarding CITED4-mediated adaptation. RNA sequence analysis revealed widespread downregulation in expression of genes involved in mitochondrial energy transduction and ATP synthesis.9 This finding is notable given that reduced mitochondrial fatty acid oxidation and oxidative phosphorylation are well-known metabolic signatures of maladaptive cardiac remodeling.10,11 In addition, the expression of PGC-1α (peroxisome proliferator-activated receptor gamma coactivator-1α), a master regulator of genes involved in cardiac mitochondrial biogenesis and metabolism,11,12 was also downregulated in the C4KO heart post-TAC. Notably, the energy metabolic reprogramming observed in the C4KO heart occurred early (within 1 week) after the pressure overload stimulus suggesting that it was directly related to CITED4 deficiency rather than a secondary effect of severe heart failure. Previous studies have shown that mTOR signaling can regulate PGC-1α expression,13 suggesting that dysregulation of the CITED4-mTORC1 circuit may also be responsible for altered mitochondrial energetics contributing to the pathological cardiac phenotype of the C4KO mice post-TAC.The C4KO hearts also exhibited a severe fibrotic response in the context of ventricular pressure overload. This raised the question of whether CITED4 also serves to defend against cardiac fibrosis. Part of the answer came from genomic profiling in C4KO and wild-type control hearts post-TAC revealing that over 70% differentially regulated microRNAs were linked to fibrosis. An interesting group was comprised of miR30 (microRNA 30) family members that have been shown to suppress cardiac fibrosis by targeting CTGF (connective tissue growth factor) in cardiac myocytes and fibroblasts.14 miR30d (microRNA 30d) was an attractive candidate given that it is enriched in cardiac myocytes and is packaged in extracellular vesicles potentially mediating cell-cell crosstalk.15 Indeed, conditioned media from myocytes in which CITED4 was knocked down (media containing less miR30d) resulted in fibroblast activation, as evidenced by induction of myofibroblast markers in cultured fibroblasts. Conversely, media from cultured cardiac myocytes in which a miR30d mimic added in the context of CITED4 knockdown blocked myofibroblast activation.9 These results suggest that CITED4 regulates factors in cardiac myocytes, including miR30, that serve as paracrine mediators to suppress cardiac fibroblast activation. Lastly, inhibition of miR30d in hearts of mice using locked nucleic acid antisense technology resulted in worsened cardiac fibrosis and dysfunction post-TAC.9The interesting results of this work9 provide new insights into the concept of adaptive cardiac remodeling. First, CITED4 was shown to be a key player in physiological cardiac hypertrophy. Second, and most surprisingly, CITED4 serves to defend against pathological cardiac remodeling. This finding overturns the simplified dogma that all aspects of the hypertrophic growth response to pathophysiological stress, such as pressure overload, are maladaptive. Third, this work supports the existence of an adaptive cascade downstream of CITED4 that is triggered during either physiological or pathological hypertrophy (Figure). Specifically, CITED4 is activated by unknown upstream signals in the context of a hypertrophic stimulus to activate mTOR signaling leading to downstream growth responses and activation of mitochondrial function via PGC-1α along with induction of miR30d (and likely other factors) to suppress fibroblast activation and possibly other inflammatory events. Given the highly adaptive nature of this response, it is possible that components of this circuitry could prove to be therapeutic targets for the prevention or treatment of heart failure.Download figureDownload PowerPointFigure. A model for regulation of adaptive cardiac hypertrophy by CITED4 (CBP/[CREB-binding protein] p300-interacting transactivators with E [glutamic acid]/D [aspartic acid]-rich-carboxyterminal domain 4). CITED4 is induced during both physiological and pathological cardiac hypertrophic growth. In cardiomyocytes, CITED4 activates mTOR activity by suppressing REDD (regulated in development and DNA damage response) expression (and possibly via other mechanisms), a known mTOR suppressor, leading to increased protein synthesis and inhibition of autophagy. The activation of mTOR (mammalian target of rapamycin) may also activate PGC-1α (peroxisome proliferator-activated receptor gamma coactivator-1α) expression, a master regulator of mitochondrial biogenesis and metabolism, leading to enhanced mitochondrial fuel oxidation and ATP-producing capacity. CITED4 also regulates expression of miR30d (microRNA 30d) which acts as a paracrine factor to suppress myofibroblast activation.As with all interesting and provocative studies, several questions are raised by the Lerchenmuller et al9 study including (1) What are the upstream events that regulate CITED4? (2) Are there CITED4 partner proteins in addition to CBP/p300 in the cardiomyocyte? (3) Are there suppressors of fibroblast activation, in addition to miR30d, downstream of CITED4? (4) Is mTOR signaling the direct connection between CITED4 and the PGC-1α–mediated control of mitochondrial function? Such questions have become highly relevant now that the case for adaptive remodeling has been CITED(4).Sources of FundingD.P. Kelly is supported by National Institutes of Health R01HL128349, R01HL058493, and R01HL151345.DisclosuresNone.FootnotesFor Sources of Funding and Disclosures, see page 649.The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Correspondence to: Daniel P. Kelly, MD, Perelman School of Medicine, University of Pennsylvania 3400 Civic Center Blvd, Bldg 421, Smilow Translational Research Center, Room 11-122 Philadelphia, PA 19104. Email [email protected]upenn.eduReferences1. Nakamura M, Sadoshima J. 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Andersson L, Cinato M, Mardani I, Miljanovic A, Arif M, Koh A, Lindbom M, Laudette M, Bollano E, Omerovic E, Klevstig M, Henricsson M, Fogelstrand P, Swärd K, Ekstrand M, Levin M, Wikström J, Doran S, Hyötyläinen T, Sinisalu L, Orešič M, Tivesten Å, Adiels M, Bergo M, Proia R, Mardinoglu A, Jeppsson A, Borén J and Levin M (2021) Glucosylceramide synthase deficiency in the heart compromises β1-adrenergic receptor trafficking, European Heart Journal, 10.1093/eurheartj/ehab412, 42:43, (4481-4492), Online publication date: 14-Nov-2021. Related articlesCITED4 Protects Against Adverse Remodeling in Response to Physiological and Pathological StressCarolin Lerchenmüller, et al. Circulation Research. 2020;127:631-646 August 14, 2020Vol 127, Issue 5 Advertisement Article InformationMetrics © 2020 American Heart Association, Inc.https://doi.org/10.1161/CIRCRESAHA.120.317623PMID: 32790523 Originally publishedAugust 13, 2020 KeywordscardiomyopathiesEditorialsmitochondriaheart failurehypertrophyPDF download Advertisement
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