Primary Cilia in Acquired Heart Disease: History
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Subjects: Cardiac & Cardiovascular Systems | Cell Biology | Biochemistry & Molecular Biology
Contributor:
Zachariah Hale

Primary cilia are non-motile plasma membrane extrusions that display a variety of receptors and mechanosensors. Loss of function results in ciliopathies, which have been strongly linked with congenital heart disease, as well as abnormal development and function of most organ systems. 

  • primary cilia
  • congenital heart disease
  • ciliopathy
  • cardiomyopathy
  • heart failure

1. Primary Cilia

1.1. Cilia Structure and Components

Primary cilia are extrusions of the plasma membrane that display a variety of receptors and mechanosensors. The core structure is an axoneme of nine doublet microtubules that extend from a basal body, and they are therefore referred to as “9 + 0” cilia. This distinguishes them from motile “9 + 2” cilia, which have an additional two dynein-associated central microtubules, permitting motion.[1]

As primary cilia do not intrinsically have associated ribosomes, they instead rely on the intraflagellar transport (IFT) system to ferry receptors and other proteins into and out of the cilium.[2] This system is capable of bidirectional movement along the length of the flagella, between the outer doublet of microtubules and the flagellar membrane.[3][4] IFT proteins, especially Ift88, are often knockout targets in cilia research, as their inactivation results in the absence of primary cilia in the affected cell.[5][6]

At the base of the cilium, near the basal body, an interactome of proteins, coined CPLANE, is responsible for ciliogenesis and intraflagellar transport. (Figure 1) These proteins act at the basal body to recruit IFT-A proteins to the base of the cilium and stabilize and insert complete IFT-A particles into the axoneme. Mutations in these proteins have been associated with a variety of ciliopathies.[4] Numerous other membrane-bound proteins located along the cilia have been associated with ciliopathies as well, including polycystins, known for causing autosomal dominant polycystic kidney disease, and septins, which have been linked with a variety of cancers and neurodegenerative conditions.[7][8][9][10][11][12].
 
Figure 1. Primary cilia structure and components. Primary cilia are an extrusion from the cell wall capable of displaying numerous proteins, including those depicted here and many others, and are supported by nine doublet microtubules arising from the basal body. IFT proteins ferry components along the length of the cilia, while the CPLANE interactome remains at the base of the cilia.

1.2. Ciliopathies

For classification purposes, first-order ciliopathies are those diseases which occur due to a mutation in genes required for the proper assembly, maintenance, or function of the cilia or the related centriole; second-order ciliopathies occur due to dysregulation of further upstream factors, such as the nuclear transcription factors Atf3, Tsc22d4, and Cbx5.[13][14] There are at least 300–1000 first-order, and many more second-order, genes.[13][15][16]

Primary cilia play an important role in most mammalian organ systems, so ciliopathies tend to display a variety of multiorgan dysfunction phenotypes. Bardet—Biedl syndrome, for example, is characterized by retinitis pigmentosa, obesity, polydactyly, cognitive impairment, and renal failure.[17] Most ciliopathies show some amount of brain, craniofacial, or endocrine dysfunction, though kidney, reproductive, and heart tissues are also often involved.[13]
One of primary cilia’s most important roles, and part of the reason mutations cause such varied phenotypes, is the display of receptors important for cell signaling pathways and the machinery for signal transduction.[18] One of the best studied is Hedgehog (Hh), which is highly dependent on functional primary cilia.[6][19][20][21] The transmembrane protein Smoothened (Smo), which is responsible for Gli protein activation in the Hh pathway, is found at the tip of the cilium.[22] Other pathways, such as Wnt, Notch, and PCP, similarly depend on primary cilia, and ciliopathies can impair their function.[23][24]
Autophagy and programmed cell death pathways, which are important for tissue homeostasis and are perturbed in neurodegenerative diseases and cancer, depend on proper ciliary function due to machinery localization to the cilia and interdependent feedback mechanisms.[23] Loss of primary cilia function results in excess cell death from autophagy in mitochondrial stress responses and from mitochondria-dependent apoptosis.[25][26] Finally, extracellular matrix makeup is sensed and regulated through primary cilia.[27][28]

1.3. Primary Cilia Locations

Despite their importance for many cellular pathways, primary cilia have not been identified on all cardiac cell types. Primary cilia are displayed on fibroblasts in the heart,[29] as well as on vascular endothelial cells, though expression on valvular endothelium decreases over time, from abundance in embryologic samples to near absence in adult samples.[30][31][32] Most cardiac interstitial (mesenchymal) cells also display primary cilia.[32] Cardiomyocytes contain primary cilia in embryonic tissue samples and lack them in adult samples, but there is disagreement regarding their presence on neonatal samples,[29][33]  suggesting a possible loss of primary cilia over time.

2. Primary Cilia in Acquired Heart Disease

2.1. Acquired Valvular Heart Disease

The importance of proper cilia function in the embryonic heart has been well established.[34][6][35][36] In a comprehensive analysis of over 87,000 mutagenized mouse fetuses, Li et al. identified 61 genes in which mutations were capable of producing echocardiographically identifiable congenital heart defects, and 35 of these genes encoded either motile or primary cilia proteins. An additional 16 genes were involved in cilia-transduced cell signaling, and 10 regulated vesicular trafficking, which is necessary for proper cilia function.[34]

Unlike the congenital defects analyzed by Li et al., mitral valve prolapse (MVP) is not evident on echocardiogram at birth. Instead, it is unusual in infants and children and it is more frequently identified in patients aged 30–80 years of age.[37] This valve pathology is a result of myxomatous degeneration over the lifetime of the patient.
In a genome-wide association study, enrichment for cilia genes was found in patients with MVP, and murine homozygous mutants of the two known familial MVP genes, Dchs1 and Flna, showed decreased primary cilia length on the neonatal mitral valve leaflets.[32][38] Exploring cilia’s mechanistic role in MVP, Toomer et al. showed that the presence of primary cilia on endocardial cells correlated with increased proteoglycan and decreased collagen in the extracellular matrix of valve endocardium. Conditional knockout of intraflagellar transport protein 88 (Ift88) in cardiac endothelial cells in mice resulted in decreased primary cilia counts, increased proteoglycans, and fragmented collagen, for example, the initiation of myxomatous degeneration.[32][39] While primary cilia abundance on valvular endothelium decreases with age, their effect on the extracellular matrix persists. As adults, these mice show myxomatous mitral valve disease.[32]

2.2. Fibrosis

In addition to myxomatous degeneration of the valve, patients with MVP also show progressive left ventricular fibrosis. Cardiac fibrosis is an excessive production and deposition of scar tissue, often a result of conditions such as hypertension or diabetes mellitus, and can lead to increased tissue stiffness, cardiomyocyte atrophy, and arrhythmias.[40][41] The fibrosis observed with MVP is more significant than that seen in patients with primary mitral valve regurgitation from a non-MVP etiology, which may suggest a common cause for both excessive fibrosis and MVP.[42]

In cardiac fibroblasts, activation of the transforming growth factor β-1 (TGF-β1) receptor results in production of fibronectin, collagen type I, and collagen type III, which are necessary components of the extracellular matrix in fibrotic tissue.[43] Fibroblasts also undergo transformation to myofibroblasts, which express α-smooth muscle actin (α-SMA) and display contractile ability.
Inactivation of primary cilia by small interference RNA (siRNA) silencing of Polycystin-1 (PC1) in fibroblasts results in a lack of upregulated collagen production in response to TGF-β1. Similarly, siRNA silencing of either PC1 or Ift88 in cardiac fibroblasts results in failure of the fibroblasts to differentiate into myofibroblasts capable of contractile function, which is necessary for standard cardiac remodeling. These mice instead show excess myocardial hypertrophy and altered scar architecture.[29]

In addition to native cardiac fibroblast proliferation, endothelial-mesenchymal transition (EndMT) is now recognized as an important source of fibroblasts for perivascular and subendocardial fibrosis.[44] Knockdown of Ift88 in endothelial cells, which results in the absence of primary cilia on these cells, appears to be insufficient to directly induce EndMT in vivo but may prime these cells for EndMT in response to lower stress than would otherwise be required.[45][46]

2.3. Vascular Pathology and Cilia

In addition to their role in fibrosis after an ischemic injury, primary cilia also regulate atherosclerosis and, therefore, the risk of ischemic events. Primary cilia serve as mechanosensors in a variety of cell types.[47] In endothelial cells with functional primary cilia, excess shear stress stimulates PC1 interaction with Polycystin-2 (PC2), permitting calcium influx and activating calcium-dependent signaling molecules, including calmodulin and calcium-dependent protein kinase (PKC), that lead to activation of endothelial nitric oxide synthetase (eNOS) and subsequent vasodilation.[48][49][50]
Branch points and the lesser curvature of the aorta are at particular risk of atherosclerosis due to relatively low and oscillatory shear stress.[51] These areas also display increased density and stability of primary cilia.[52][53] Initial research suggested that primary cilia may play a role in producing atherosclerosis, as apolipoprotein-E-deficient (Apoe−/−) mice display increased primary cilia as well as increased atherosclerosis at these risk points.[39] However, removing these cilia via knockout of Ift88 results in increased atherosclerosis in Apoe−/− mice in response to a high fat, high cholesterol diet, suggesting this is a protective response mediated by eNOS.[54]
PC1 and PC2 gene mutations produce autosomal dominant polycystic kidney disease (ADPKD), which results in hypertension in two-thirds of cases.[55] In addition to the eNOS activation mechanism, primary cilia also protect against hypertension via dopamine receptor 5 (DR5).[50][56] Stimulation at this receptor results in adenylyl cyclase and PKC activation, leading to vasodilation.[57]

2.4. Ventricular Remodeling and Recovery

Cardiomyocyte hypertrophy is an important cell autonomous and non-cell autonomous adaptive response to significant stress, especially hypertension, that is necessary for survival. However prolonged stress and resultant excess hypertrophy and cardiac remodeling can lead to heart failure and sudden cardiac death.[58][59][60] Cardiomyocytes have some ability to sense mechanical forces, including hemodynamic stress, in order to convert stress into intracellular growth signals and induce hypertrophy. However, the molecular identity of the mechanosensor remains elusive. Primary cilia are an attractive candidate as a mechanosensor; however, this has not been demonstrated experimentally.

One possible mechanism appears to be via ciliary extracellular-like vesicles (cELVs).[61] These vesicles are released from cilia under normal circumstances and at increased rates under fluid shear stress. Blocking ciliary proteins necessary for cELV production using short hairpin RNA (shRNA) prevents cELV production and results in left ventricular hypertrophy, decreasing left ventricular ejection fraction, and, eventually, low blood pressure and cardiovascular collapse.[61][62]

2.5. Congenital Heart Disease and Late-Onset Heart Failure

Patients with CHD show a higher risk of heart failure later in life than patients born with grossly normal hearts.[63][64][65] it was showed an overall prevalence of heart failure of 26% in a cohort of patients with surgically corrected congenital heart disease (CHD).[65] While the highest risk of heart failure is in patients with morphologically right ventricles exposed to systemic pressures, even patients with isolated ventricular septal defect are at higher risk of systolic and diastolic dysfunction 30 or more years after surgical repair.[66] This suggests that either a factor of the surgery can produce ventricular dysfunction decades later, such as the residual scar tissue, or else that a common etiology for both the CHD and ventricular dysfunction exists.
Some familial CHD-producing gene mutations have also been associated with ventricular dysfunction, such as the sarcomeric gene MYH7.[64] However, it are not aware of any current published research directly linking primary cilia gene mutations with heart failure through a mechanism different than those discussed above. While primary cilia are not displayed on adult cardiomyocytes, many ciliary proteins continue to exist and function at non-cilia locations, and cilia continue to be present in other cell types. Acquired ventricular dysfunction may therefore be mediated by ciliated non-myocytes, or else via cilia-independent functions of cilia proteins in cardiomyocytes. Alternatively, ciliogenesis may be reactivated in de-differentiated cardiomyocytes or cardiomyocyte progenitor cells in response to stress. Another possibility is that primary cilia defects in the developing heart result in permanent differences in the adult myocytes’ response to the stresses discussed above. Additional research is needed to identify the role of primary cilia in heart failure.

This entry is adapted from the peer-reviewed paper 10.3390/cells11060960

References

  1. Peter Satir; Lotte B. Pedersen; Søren T. Christensen; The primary cilium at a glance. Journal of Cell Science 2010, 123, 499-503, 10.1242/jcs.050377.
  2. Andrew M Fry; Michelle J Leaper; Richard Bayliss; The primary cilium. Organogenesis 2013, 10, 62-68, 10.4161/org.28910.
  3. K G Kozminski; K A Johnson; P Forscher; J L Rosenbaum; A motility in the eukaryotic flagellum unrelated to flagellar beating.. Proceedings of the National Academy of Sciences 1993, 90, 5519-5523, 10.1073/pnas.90.12.5519.
  4. Michinori Toriyama; University of Washington Center for Mendelian Genomics; Chanjae Lee; S Paige Taylor; Ivan Duran; Daniel H Cohn; Ange-Line Bruel; Jacqueline M Tabler; Kevin Drew; Marcus Kelly; et al. The ciliopathy-associated CPLANE proteins direct basal body recruitment of intraflagellar transport machinery. Nature Genetics 2016, 48, 648-656, 10.1038/ng.3558.
  5. Vincent Z. Luu; Albert Z. Luu; Biswajit Chowdhury; Omar Elbardisy; Yi Pan; Mohammed Al-Omran; Adrian Quan; Hwee Teoh; David A. Hess; Subodh Verma; et al. Disruption of endothelial cell intraflagellar transport protein 88 exacerbates doxorubicin-induced cardiotoxicity. Life Sciences 2020, 260, 118216, 10.1016/j.lfs.2020.118216.
  6. Marc August Willaredt; Karin Gorgas; Humphrey A R Gardner; Kerry L Tucker; Multiple essential roles for primary cilia in heart development. Cilia 2012, 1, 23-23, 10.1186/2046-2530-1-23.
  7. Kelsey Moore; Reece Moore; Christina Wang; Russell A. Norris; Tugging at the Heart Strings: The Septin Cytoskeleton in Heart Development and Disease. Journal of Cardiovascular Development and Disease 2020, 7, 3, 10.3390/jcdd7010003.
  8. Dominique Douguet; Amanda Patel; Eric Honoré; Structure and function of polycystins: insights into polycystic kidney disease. Nature Reviews Nephrology 2019, 15, 412-422, 10.1038/s41581-019-0143-6.
  9. K Kojima; I Sakai; A Hasegawa; H Niiya; T Azuma; Y Matsuo; N Fujii; M Tanimoto; S Fujita; FLJ10849, a septin family gene, fuses MLL in a novel leukemia cell line CNLBC1 derived from chronic neutrophilic leukemia in transformation with t(4;11)(q21;q23). Leukemia 2004, 18, 998-1005, 10.1038/sj.leu.2403334.
  10. Dimitrios Angelis; Elias T. Spiliotis; Septin Mutations in Human Cancers. Frontiers in Cell and Developmental Biology 2016, 4, 122, 10.3389/fcell.2016.00122.
  11. Ayae Kinoshita; Makoto Kinoshita; Haruhiko Akiyama; Hidekazu Tomimoto; Ichiro Akiguchi; Sharad Kumar; Makoto Noda; Jun Kimura; Identification of Septins in Neurofibrillary Tangles in Alzheimer's Disease. The American Journal of Pathology 1998, 153, 1551-1560, 10.1016/s0002-9440(10)65743-4.
  12. Italo A. Cavini; Diego A. Leonardo; Higor V. D. Rosa; Danielle K. S. V. Castro; Humberto D’Muniz Pereira; Napoleão F. Valadares; Ana P. U. Araujo; Richard C. Garratt; The Structural Biology of Septins and Their Filaments: An Update. Frontiers in Cell and Developmental Biology 2021, 9, 1, 10.3389/fcell.2021.765085.
  13. Marta Lovera; Jens Lüders; The ciliary impact of nonciliary gene mutations. Trends in Cell Biology 2021, 31, 876-887, 10.1016/j.tcb.2021.06.001.
  14. Gabrielle Wheway; UK10K Consortium; Miriam Schmidts; Dorus A. Mans; Katarzyna Szymanska; Thanh-Minh T. Nguyen; Hilary Racher; Ian G. Phelps; Grischa Toedt; Julie Kennedy; et al. An siRNA-based functional genomics screen for the identification of regulators of ciliogenesis and ciliopathy genes. Nature Cell Biology 2015, 17, 1074-1087, 10.1038/ncb3201 [doi].
  15. John van Dam; SYSCILIA Study Group; Gabrielle Wheway; Gisela G Slaats; Martijn Huynen; Rachel H Giles; The SYSCILIA gold standard (SCGSv1) of known ciliary components and its applications within a systems biology consortium. Cilia 2013, 2, 1, 10.1186/2046-2530-2-7 [doi].
  16. Teunis J. P. van Dam; Julie Kennedy; Robin van der Lee; Erik de Vrieze; Kirsten A. Wunderlich; Suzanne Rix; Gerard W. Dougherty; Nils J. Lambacher; Chunmei Li; Victor L. Jensen; et al. CiliaCarta: An integrated and validated compendium of ciliary genes. PLoS ONE 2019, 14, e0216705, 10.1371/journal.pone.0216705.
  17. Clarisse Delvallée; Samuel Nicaise; Manuela Antin; Anne‐Sophie Leuvrey; Elsa Nourisson; Carmen C. Leitch; Georgios Kellaris; Corinne Stoetzel; Véronique Geoffroy; Sophie Scheidecker; et al. A BBS1 SVA F retrotransposon insertion is a frequent cause of Bardet‐Biedl syndrome. Clinical Genetics 2020, 99, 318-324, 10.1111/cge.13878.
  18. Jarema J. Malicki; Colin A. Johnson; The Cilium: Cellular Antenna and Central Processing Unit. Trends in Cell Biology 2016, 27, 126-140, 10.1016/j.tcb.2016.08.002.
  19. Ganesh V. Pusapati; Jennifer Kong; Bhaven B. Patel; ArunKumar Krishnan; Andreas Sagner; Maia Kinnebrew; James Briscoe; L. Aravind; Rajat Rohatgi; CRISPR Screens Uncover Genes that Regulate Target Cell Sensitivity to the Morphogen Sonic Hedgehog. Developmental Cell 2017, 44, 113-129.e8, 10.1016/j.devcel.2017.12.003.
  20. David K. Breslow; Sascha Hoogendoorn; Adam R. Kopp; David W. Morgens; Brandon K. Vu; Margaret C. Kennedy; Kyuho Han; Amy Li; Gaelen T. Hess; Michael C. Bassik; et al. A CRISPR-based screen for Hedgehog signaling provides insights into ciliary function and ciliopathies. Nature Genetics 2018, 50, 460-471, 10.1038/s41588-018-0054-7.
  21. Lasse Jonsgaard Larsen; Lisbeth Birk Møller; Crosstalk of Hedgehog and mTORC1 Pathways. Cells 2020, 9, 2316, 10.3390/cells9102316.
  22. Fiona Bangs; Kathryn V. Anderson; Primary Cilia and Mammalian Hedgehog Signaling. Cold Spring Harbor Perspectives in Biology 2016, 9, a028175, 10.1101/cshperspect.a028175.
  23. Manuela Morleo; Brunella Franco; The Autophagy-Cilia Axis: An Intricate Relationship.. Cells 2019, 8, 905, 10.3390/cells8080905.
  24. Sarah C. Goetz; Kathryn Anderson; The primary cilium: a signalling centre during vertebrate development. Nature Reviews Genetics 2010, 11, 331-344, 10.1038/nrg2774.
  25. Ji-Eun Bae; Gil Myung Kang; Se Hee Min; Doo Sin Jo; Yong-Keun Jung; Keetae Kim; Min-Seon Kim; Dong-Hyung Cho; Primary cilia mediate mitochondrial stress responses to promote dopamine neuron survival in a Parkinson’s disease model. Cell Death & Disease 2019, 10, 1-15, 10.1038/s41419-019-2184-y.
  26. Junguee Lee; Ki Cheol Park; Hae Joung Sul; Hyun Jung Hong; Kun-Ho Kim; Jukka Kero; Minho Shong; Loss of primary cilia promotes mitochondria-dependent apoptosis in thyroid cancer. Scientific Reports 2021, 11, 1-15, 10.1038/s41598-021-83418-3.
  27. Kimberly F. Atkinson; Rinzhin T. Sherpa; Surya M. Nauli; The Role of the Primary Cilium in Sensing Extracellular pH.. Cells 2019, 8, 704, 10.3390/cells8070704.
  28. Collins I; Wann A.K.T; Isabella Collins; A.K.T Wann; Regulation of the Extracellular Matrix by Ciliary Machinery. Cells 2020, 9, 278, 10.3390/cells9020278.
  29. Elisa Villalobos; Alfredo Criollo; Gabriele Schiattarella; Francisco Altamirano; Kristin M. French; Herman May; Nan Jiang; Ngoc Uyen Nhi Nguyen; Diego Romero; Juan Carlos Roa; et al. Fibroblast Primary Cilia Are Required for Cardiac Fibrosis. Circulation 2019, 139, 2342-2357, 10.1161/circulationaha.117.028752.
  30. Xinhua Li; Shuting Yang; Vishwa Deepak; Zahra Chinipardaz; Shuying Yang; Identification of Cilia in Different Mouse Tissues. Cells 2021, 10, 1623, 10.3390/cells10071623.
  31. Hua Zhang; Dan Chalothorn; James E Faber; Collateral Vessels Have Unique Endothelial and Smooth Muscle Cell Phenotypes. International Journal of Molecular Sciences 2019, 20, 3608, 10.3390/ijms20153608.
  32. Katelynn A. Toomer; Mengyao Yu; Diana Fulmer; Lilong Guo; Kelsey S. Moore; Reece Moore; Ka’La D. Drayton; Janiece Glover; Neal Peterson; Sandra Ramos-Ortiz; et al. Primary cilia defects causing mitral valve prolapse. Science Translational Medicine 2019, 11, 1, 10.1126/scitranslmed.aax0290.
  33. Sarbjot Kaur; Sue R. McGlashan; Marie-Louise Ward; Evidence of primary cilia in the developing rat heart. Cilia 2018, 7, 1-7, 10.1186/s13630-018-0058-z.
  34. You Li; Nikolai T. Klena; George C. Gabriel; Xiaoqin Liu; Andrew J. Kim; Kristi Lemke; Yu Chen; Bishwanath Chatterjee; William Devine; Rama Rao Damerla; et al. Global genetic analysis in mice unveils central role for cilia in congenital heart disease. Nature 2015, 521, 520-524, 10.1038/nature14269.
  35. Kylia Williams; Jason Carson; Cecilia Lo; Genetics of Congenital Heart Disease. Biomolecules 2019, 9, 879, 10.3390/biom9120879.
  36. Diana Fulmer; Katelynn Toomer; Lilong Guo; Kelsey Moore; Janiece Glover; Reece Moore; Rebecca Stairley; Glenn Lobo; Xiaofeng Zuo; Yujing Dang; et al. Defects in the Exocyst-Cilia Machinery Cause Bicuspid Aortic Valve Disease and Aortic Stenosis. Circulation 2019, 140, 1331-1341, 10.1161/circulationaha.119.038376.
  37. Francesca N. Delling; Ramachandran S. Vasan; Epidemiology and Pathophysiology of Mitral Valve Prolapse. Circulation 2014, 129, 2158-2170, 10.1161/circulationaha.113.006702.
  38. Ronen Durst; Kimberly Sauls; David S. Peal; Annemarieke DeVlaming; Katelynn Toomer; Maire Leyne; Monica Salani; Michael Talkowski; Harrison Brand; Maëlle Perrocheau; et al. Mutations in DCHS1 cause mitral valve prolapse. Nature 2015, 525, 109-113, 10.1038/nature14670.
  39. Katelynn A Toomer; Diana Fulmer; Lilong Guo; Alex Drohan; Neal Peterson; Paige Swanson; Brittany Brooks; Rupak Mukherjee; Simon Body; Joshua H. Lipschutz; et al. A role for primary cilia in aortic valve development and disease. Developmental Dynamics 2017, 246, 625-634, 10.1002/dvdy.24524.
  40. Andrew Leask; Getting to the Heart of the Matter. Circulation Research 2015, 116, 1269-1276, 10.1161/circresaha.116.305381.
  41. Robert A. Levine; Michael Jerosch-Herold; Roger J. Hajjar; Mitral Valve Prolapse. Journal of the American College of Cardiology 2018, 72, 835-837, 10.1016/j.jacc.2018.07.006.
  42. Danai Kitkungvan; Faisal Nabi; Raymond J. Kim; Robert O. Bonow; Ahmad Khan; Jiaqiong Xu; Stephen H. Little; Miguel A. Quinones; Gerald M. Lawrie; William A. Zoghbi; et al. Myocardial Fibrosis in Patients With Primary Mitral Regurgitation With and Without Prolapse. Journal of the American College of Cardiology 2018, 72, 823-834, 10.1016/j.jacc.2018.06.048.
  43. Marcin Dobaczewski; Judith J. de Haan; Nikolaos G. Frangogiannis; The Extracellular Matrix Modulates Fibroblast Phenotype and Function in the Infarcted Myocardium. Journal of Cardiovascular Translational Research 2012, 5, 837-847, 10.1007/s12265-012-9406-3.
  44. Elisabeth M Zeisberg; Oleg Tarnavski; Michael Zeisberg; Adam L Dorfman; Julie R McMullen; Erika Gustafsson; Anil Chandraker; Xueli Yuan; William T Pu; Anita B Roberts; et al. Endothelial-to-mesenchymal transition contributes to cardiac fibrosis. Nature Medicine 2007, 13, 952-961, 10.1038/nm1613.
  45. Shweta Singh; Mohamed Adam; Pratiek N. Matkar; Antoinette Bugyei-Twum; Jean-Francois Desjardins; Hao H. Chen; Hien Nguyen; Hannah Bazinet; David Michels; Zongyi Liu; et al. Endothelial-specific Loss of IFT88 Promotes Endothelial-to-Mesenchymal Transition and Exacerbates Bleomycin-induced Pulmonary Fibrosis. Scientific Reports 2020, 10, 1-14, 10.1038/s41598-020-61292-9.
  46. Anastasia D. Egorova; Padmini P.S.J. Khedoe; Marie-José T.H. Goumans; Bradley K. Yoder; Surya M. Nauli; Peter Ten Dijke; Robert E. Poelmann; Beerend P. Hierck; Lack of Primary Cilia Primes Shear-Induced Endothelial-to-Mesenchymal Transition. Circulation Research 2011, 108, 1093-1101, 10.1161/CIRCRESAHA.110.231860.
  47. Milos Spasic; Christopher R. Jacobs; Primary cilia: Cell and molecular mechanosensors directing whole tissue function. Seminars in Cell & Developmental Biology 2017, 71, 42-52, 10.1016/j.semcdb.2017.08.036.
  48. Vincent Z. Luu; Biswajit Chowdhury; Mohammed Al-Omran; David A. Hess; Subodh Verma; Role of endothelial primary cilia as fluid mechanosensors on vascular health. Atherosclerosis 2018, 275, 196-204, 10.1016/j.atherosclerosis.2018.06.818.
  49. Surya M. Nauli; Yoshifumi Kawanabe; John J. Kaminski; William J. Pearce; Donald E. Ingber; Jing Zhou; Endothelial Cilia Are Fluid Shear Sensors That Regulate Calcium Signaling and Nitric Oxide Production Through Polycystin-1. Circulation 2008, 117, 1161-1171, 10.1161/circulationaha.107.710111.
  50. Rajasekharreddy Pala; Maha Jamal; Qamar Alshammari; Surya M. Nauli; The Roles of Primary Cilia in Cardiovascular Diseases.. Cells 2018, 7, 233, 10.3390/cells7120233.
  51. Caroline Cheng; Dennie Tempel; Rien Van Haperen; Arjen Van Der Baan; Frank Grosveld; Mat Daemen; Rob Krams; Rini De Crom; Atherosclerotic Lesion Size and Vulnerability Are Determined by Patterns of Fluid Shear Stress. Circulation 2006, 113, 2744-2753, 10.1161/circulationaha.105.590018.
  52. Kim van der Heiden; Beerend Hierck; Rob Krams; Rini de Crom; Caroline Cheng; Martin Baiker; Mathieu J.B.M. Pourquie; Fanneke E. Alkemade; Marco C. DeRuiter; Adriana C. Gittenberger-De Groot; et al. Endothelial primary cilia in areas of disturbed flow are at the base of atherosclerosis. Atherosclerosis 2008, 196, 542-550, 10.1016/j.atherosclerosis.2007.05.030.
  53. Lina C. Espinha; David Hoey; Paulo Rui Fernandes; Helder Rodrigues; Christopher R. Jacobs; Oscillatory fluid flow influences primary cilia and microtubule mechanics. Cytoskeleton 2014, 71, 435-445, 10.1002/cm.21183.
  54. Colin Dinsmore; Jeremy F Reiter; Endothelial primary cilia inhibit atherosclerosis. EMBO reports 2016, 17, 156-166, 10.15252/embr.201541019.
  55. Christine Patch; Judith Charlton; Paul J. Roderick; Martin C. Gulliford; Use of Antihypertensive Medications and Mortality of Patients With Autosomal Dominant Polycystic Kidney Disease: A Population-Based Study. American Journal of Kidney Diseases 2011, 57, 856-862, 10.1053/j.ajkd.2011.01.023.
  56. Shakila Abdul-Majeed; Surya M. Nauli; Dopamine Receptor Type 5 in the Primary Cilia Has Dual Chemo- and Mechano-Sensory Roles. Hypertension 2011, 58, 325-331, 10.1161/hypertensionaha.111.172080.
  57. Chunyu Zeng; Pedro A. Jose; Dopamine Receptors. Hypertension 2010, 57, 11-17, 10.1161/hypertensionaha.110.157727.
  58. N. Frey; E.N. Olson; Cardiac Hypertrophy: The Good, the Bad, and the Ugly. Annual Review of Physiology 2003, 65, 45-79, 10.1146/annurev.physiol.65.092101.142243 092101.142243.
  59. Norifumi Takeda; Ichiro Manabe; Yuichi Uchino; Kosei Eguchi; Sahohime Matsumoto; Satoshi Nishimura; Takayuki Shindo; Motoaki Sano; Kinya Otsu; Paige Snider; et al. Cardiac fibroblasts are essential for the adaptive response of the murine heart to pressure overload. Journal of Clinical Investigation 2010, 120, 254-265, 10.1172/jci40295.
  60. Mary J. Roman; Antonello Ganau; Pier Sergio Saba; Riccardo Pini; Thomas G. Pickering; Richard B. Devereux; Impact of Arterial Stiffening on Left Ventricular Structure. Hypertension 2000, 36, 489-494, 10.1161/01.hyp.36.4.489.
  61. Ann-Kathrin Volz; Alina Frei; Viola Kretschmer; António M. De Jesus Domingues; Rene F. Ketting; Marius Ueffing; Karsten Boldt; Eva-Maria Krämer-Albers; Helen L. May-Simera; Bardet-Biedl syndrome proteins modulate the release of bioactive extracellular vesicles. Nature Communications 2021, 12, 1-16, 10.1038/s41467-021-25929-1.
  62. Ashraf M. Mohieldin; Rajasekharreddy Pala; Rinzhin T. Sherpa; Madhawi Alanazi; Ashwaq Alanazi; Kiumars Shamloo; Amir Ahsan; Wissam A. AbouAlaiwi; James J. Moresco; John R. Yates; et al. Proteomic Identification Reveals the Role of Ciliary Extracellular‐Like Vesicle in Cardiovascular Function. Advanced Science 2020, 7, 1903140, 10.1002/advs.201903140.
  63. Thomas P Graham; Yvonne D Bernard; Beverly G Mellen; David Celermajer; Helmut Baumgartner; Frank Cetta; Heidi M Connolly; William R Davidson; Mikael Dellborg; Elyse Foster; et al. Long-term outcome in congenitally corrected transposition of the great arteries: A multi-institutional study. Journal of the American College of Cardiology 2000, 36, 255-261, 10.1016/s0735-1097(00)00682-3.
  64. Robert B. Hinton; Stephanie M. Ware; Heart Failure in Pediatric Patients With Congenital Heart Disease. Circulation Research 2017, 120, 978-994, 10.1161/circresaha.116.308996.
  65. Kambiz Norozi; Armin Wessel; Valentin Alpers; Jan Ole Arnhold; Siegfried Geyer; Monika Zoege; Reiner Buchhorn; Incidence and Risk Distribution of Heart Failure in Adolescents and Adults With Congenital Heart Disease After Cardiac Surgery. The American Journal of Cardiology 2006, 97, 1238-1243, 10.1016/j.amjcard.2005.10.065.
  66. Myrthe E. Menting; Judith A.A.E. Cuypers; Petra Opić; Elisabeth M.W.J. Utens; Maarten Witsenburg; Annemien E. Van Den Bosch; Ron T. van Domburg; Folkert J. Meijboom; Eric Boersma; Ad J.J.C. Bogers; et al. The Unnatural History of the Ventricular Septal Defect. Journal of the American College of Cardiology 2015, 65, 1941-1951, 10.1016/j.jacc.2015.02.055.
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