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3.
J Biol Chem ; 299(12): 105426, 2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-37926281

RESUMEN

S-palmitoylation is a reversible lipid modification catalyzed by 23 S-acyltransferases with a conserved zinc finger aspartate-histidine-histidine-cysteine (zDHHC) domain that facilitates targeting of proteins to specific intracellular membranes. Here we performed a gain-of-function screen in the mouse and identified the Golgi-localized enzymes zDHHC3 and zDHHC7 as regulators of cardiac hypertrophy. Cardiomyocyte-specific transgenic mice overexpressing zDHHC3 show cardiac disease, and S-acyl proteomics identified the small GTPase Rac1 as a novel substrate of zDHHC3. Notably, cardiomyopathy and congestive heart failure in zDHHC3 transgenic mice is preceded by enhanced Rac1 S-palmitoylation, membrane localization, activity, downstream hypertrophic signaling, and concomitant induction of all Rho family small GTPases whereas mice overexpressing an enzymatically dead zDHHC3 mutant show no discernible effect. However, loss of Rac1 or other identified zDHHC3 targets Gαq/11 or galectin-1 does not diminish zDHHC3-induced cardiomyopathy, suggesting multiple effectors and pathways promoting decompensation with sustained zDHHC3 activity. Genetic deletion of Zdhhc3 in combination with Zdhhc7 reduces cardiac hypertrophy during the early response to pressure overload stimulation but not over longer time periods. Indeed, cardiac hypertrophy in response to 2 weeks of angiotensin-II infusion is not diminished by Zdhhc3/7 deletion, again suggesting other S-acyltransferases or signaling mechanisms compensate to promote hypertrophic signaling. Taken together, these data indicate that the activity of zDHHC3 and zDHHC7 at the cardiomyocyte Golgi promote Rac1 signaling and maladaptive cardiac remodeling, but redundant signaling effectors compensate to maintain cardiac hypertrophy with sustained pathological stimulation in the absence of zDHHC3/7.


Asunto(s)
Cardiomiopatías , Miocitos Cardíacos , Animales , Ratones , Aciltransferasas/genética , Aciltransferasas/metabolismo , Cardiomegalia/metabolismo , Cardiomiopatías/genética , Cardiomiopatías/metabolismo , Histidina/metabolismo , Lipoilación , Ratones Transgénicos , Miocitos Cardíacos/metabolismo
5.
Nat Commun ; 14(1): 5509, 2023 09 07.
Artículo en Inglés | MEDLINE | ID: mdl-37679366

RESUMEN

How two-chambered hearts in basal vertebrates have evolved from single-chamber hearts found in ancestral chordates remains unclear. Here, we show that the teleost sinus venosus (SV) is a chamber-like vessel comprised of an outer layer of smooth muscle cells. We find that in adult zebrafish nr2f1a mutants, which lack atria, the SV comes to physically resemble the thicker bulbus arteriosus (BA) at the arterial pole of the heart through an adaptive, hypertensive response involving smooth muscle proliferation due to aberrant hemodynamic flow. Single cell transcriptomics show that smooth muscle and endothelial cell populations within the adapting SV also take on arterial signatures. Bulk transcriptomics of the blood sinuses flanking the tunicate heart reinforce a model of greater equivalency in ancestral chordate BA and SV precursors. Our data simultaneously reveal that secondary complications from congenital heart defects can develop in adult zebrafish similar to those in humans and that the foundation of equivalency between flanking auxiliary vessels may remain latent within basal vertebrate hearts.


Asunto(s)
Enfermedades Cardiovasculares , Cordados , Adulto , Humanos , Animales , Pez Cebra/genética , Aclimatación , Arterias , Atrios Cardíacos
6.
Cells ; 12(17)2023 08 30.
Artículo en Inglés | MEDLINE | ID: mdl-37681905

RESUMEN

RATIONALE: The adult cardiac extracellular matrix (ECM) is largely comprised of type I collagen. In addition to serving as the primary structural support component of the cardiac ECM, type I collagen also provides an organizational platform for other ECM proteins, matricellular proteins, and signaling components that impact cellular stress sensing in vivo. OBJECTIVE: Here we investigated how the content and integrity of type I collagen affect cardiac structure function and response to injury. METHODS AND RESULTS: We generated and characterized Col1a2-/- mice using standard gene targeting. Col1a2-/- mice were viable, although by young adulthood their hearts showed alterations in ECM mechanical properties, as well as an unanticipated activation of cardiac fibroblasts and induction of a progressive fibrotic response. This included augmented TGFß activity, increases in fibroblast number, and progressive cardiac hypertrophy, with reduced functional performance by 9 months of age. Col1a2-loxP-targeted mice were also generated and crossed with the tamoxifen-inducible Postn-MerCreMer mice to delete the Col1a2 gene in myofibroblasts with pressure overload injury. Interestingly, while germline Col1a2-/- mice showed gradual pathologic hypertrophy and fibrosis with aging, the acute deletion of Col1a2 from activated adult myofibroblasts showed a loss of total collagen deposition with acute cardiac injury and an acute reduction in pressure overload-induce cardiac hypertrophy. However, this reduction in hypertrophy due to myofibroblast-specific Col1a2 deletion was lost after 2 and 6 weeks of pressure overload, as fibrotic deposition accumulated. CONCLUSIONS: Defective type I collagen in the heart alters the structural integrity of the ECM and leads to cardiomyopathy in adulthood, with fibroblast expansion, activation, and alternate fibrotic ECM deposition. However, acute inhibition of type I collagen production can have an anti-fibrotic and anti-hypertrophic effect.


Asunto(s)
Cardiomiopatías , Colágeno Tipo I , Animales , Ratones , Cardiomegalia/genética , Colágeno Tipo I/genética , Fibrosis
7.
bioRxiv ; 2023 Jan 07.
Artículo en Inglés | MEDLINE | ID: mdl-36711864

RESUMEN

Chronic inflammation and tissue fibrosis are common stress responses that worsen organ function, yet the molecular mechanisms governing their crosstalk are poorly understood. In diseased organs, stress-induced changes in gene expression fuel maladaptive cell state transitions and pathological interaction between diverse cellular compartments. Although chronic fibroblast activation worsens dysfunction of lung, liver, kidney, and heart, and exacerbates many cancers, the stress-sensing mechanisms initiating the transcriptional activation of fibroblasts are not well understood. Here, we show that conditional deletion of the transcription co-activator Brd4 in Cx3cr1-positive myeloid cells ameliorates heart failure and is associated with a dramatic reduction in fibroblast activation. Analysis of single-cell chromatin accessibility and BRD4 occupancy in vivo in Cx3cr1-positive cells identified a large enhancer proximal to Interleukin-1 beta (Il1b), and a series of CRISPR deletions revealed the precise stress-dependent regulatory element that controlled expression of Il1b in disease. Secreted IL1B functioned non-cell autonomously to activate a p65/RELA-dependent enhancer near the transcription factor MEOX1, resulting in a profibrotic response in human cardiac fibroblasts. In vivo, antibody-mediated IL1B neutralization prevented stress-induced expression of MEOX1, inhibited fibroblast activation, and improved cardiac function in heart failure. The elucidation of BRD4-dependent crosstalk between a specific immune cell subset and fibroblasts through IL1B provides new therapeutic strategies for heart disease and other disorders of chronic inflammation and maladaptive tissue remodeling.

8.
Cardiovasc Res ; 118(18): 3482-3498, 2023 02 03.
Artículo en Inglés | MEDLINE | ID: mdl-36004821

RESUMEN

Cardiovascular diseases and specifically heart failure (HF) impact global health and impose a significant economic burden on society. Despite current advances in standard of care, the risks for death and readmission of HF patients remain unacceptably high and new therapeutic strategies to limit HF progression are highly sought. In disease settings, persistent mechanical or neurohormonal stress to the myocardium triggers maladaptive cardiac remodelling, which alters cardiac function and structure at both the molecular and cellular levels. The progression and magnitude of maladaptive cardiac remodelling ultimately leads to the development of HF. Classical therapies for HF are largely protein-based and mostly are targeted to ameliorate the dysregulation of neuroendocrine pathways and halt adverse remodelling. More recently, investigation of novel molecular targets and the application of cellular therapies, epigenetic modifications, and regulatory RNAs has uncovered promising new avenues to address HF. In this review, we summarize the current knowledge on novel cellular and epigenetic therapies and focus on two non-coding RNA-based strategies that reached the phase of early clinical development to counteract cardiac remodelling and HF. The current status of the development of translating those novel therapies to clinical practice, limitations, and future perspectives are additionally discussed.


Asunto(s)
Insuficiencia Cardíaca , Remodelación Ventricular , Humanos , Insuficiencia Cardíaca/terapia , Insuficiencia Cardíaca/tratamiento farmacológico , Miocardio/metabolismo , Epigénesis Genética , Fibrosis
9.
Cell Stem Cell ; 29(3): 352-354, 2022 03 03.
Artículo en Inglés | MEDLINE | ID: mdl-35245466

RESUMEN

Fibrosis, or chronic fibroblast activation and extracellular matrix deposition, underlies most cardiovascular diseases and remains challenging to target therapeutically. Reported in Science by Rurik et al., modified mRNA technology can reprogram endogenous T cells into fibroblast-ablating CAR-Ts in mouse hearts, offering a promising and tractable immunotherapy approach for tackling fibrosis.


Asunto(s)
Inmunoterapia , Linfocitos T , Animales , Fibroblastos/patología , Fibrosis , Ratones , ARN Mensajero/genética
11.
Circulation ; 144(7): 539-555, 2021 08 17.
Artículo en Inglés | MEDLINE | ID: mdl-34111939

RESUMEN

BACKGROUND: Pulmonary hypertension (PH) is a common complication in patients with alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV), a severe congenital disorder associated with mutations in the FOXF1 gene. Although the loss of alveolar microvasculature causes PH in patients with ACDMPV, it is unknown whether increasing neonatal lung angiogenesis could prevent PH and right ventricular (RV) hypertrophy. METHODS: We used echocardiography, RV catheterization, immunostaining, and biochemical methods to examine lung and heart remodeling and RV output in Foxf1WT/S52F mice carrying the S52F Foxf1 mutation (identified in patients with ACDMPV). The ability of Foxf1WT/S52F mutant embryonic stem cells to differentiate into respiratory cell lineages in vivo was examined using blastocyst complementation. Intravascular delivery of nanoparticles with a nonintegrating Stat3 expression vector was used to improve neonatal pulmonary angiogenesis in Foxf1WT/S52F mice and determine its effects on PH and RV hypertrophy. RESULTS: Foxf1WT/S52F mice developed PH and RV hypertrophy after birth. The severity of PH in Foxf1WT/S52F mice directly correlated with mortality, low body weight, pulmonary artery muscularization, and increased collagen deposition in the lung tissue. Increased fibrotic remodeling was found in human ACDMPV lungs. Mouse embryonic stem cells carrying the S52F Foxf1 mutation were used to produce chimeras through blastocyst complementation and to demonstrate that Foxf1WT/S52F embryonic stem cells have a propensity to differentiate into pulmonary myofibroblasts. Intravascular delivery of nanoparticles carrying Stat3 cDNA protected Foxf1WT/S52F mice from RV hypertrophy and PH, improved survival, and decreased fibrotic lung remodeling. CONCLUSIONS: Nanoparticle therapies increasing neonatal pulmonary angiogenesis may be considered to prevent PH in ACDMPV.


Asunto(s)
Técnicas de Transferencia de Gen , Hipertensión Pulmonar/etiología , Hipertensión Pulmonar/terapia , Nanopartículas , Síndrome de Circulación Fetal Persistente/complicaciones , Alveolos Pulmonares/anomalías , Factor de Transcripción STAT3/genética , Remodelación de las Vías Aéreas (Respiratorias)/genética , Animales , Biomarcadores , Modelos Animales de Enfermedad , Susceptibilidad a Enfermedades , Portadores de Fármacos , Sistemas de Liberación de Medicamentos , Ecocardiografía , Fibrosis , Factores de Transcripción Forkhead/deficiencia , Terapia Genética , Humanos , Hipertensión Pulmonar/diagnóstico , Hipertensión Pulmonar/metabolismo , Hipertrofia Ventricular Derecha/diagnóstico , Hipertrofia Ventricular Derecha/etiología , Hipertrofia Ventricular Derecha/metabolismo , Ratones , Ratones Transgénicos , Densidad Microvascular/genética , Miofibroblastos/metabolismo , Síndrome de Circulación Fetal Persistente/genética , Síndrome de Circulación Fetal Persistente/patología , Factor de Transcripción STAT3/administración & dosificación , Nanomedicina Teranóstica/métodos , Resultado del Tratamiento , Remodelación Vascular/genética
16.
Nat Commun ; 11(1): 4549, 2020 09 11.
Artículo en Inglés | MEDLINE | ID: mdl-32917889

RESUMEN

Arterial macrophages have different developmental origins, but the association of macrophage ontogeny with their phenotypes and functions in adulthood is still unclear. Here, we combine macrophage fate-mapping analysis with single-cell RNA sequencing to establish their cellular identity during homeostasis, and in response to angiotensin-II (AngII)-induced arterial inflammation. Yolk sac erythro-myeloid progenitors (EMP) contribute substantially to adventitial macrophages and give rise to a defined cluster of resident immune cells with homeostatic functions that is stable in adult mice, but declines in numbers during ageing and is not replenished by bone marrow (BM)-derived macrophages. In response to AngII inflammation, increase in adventitial macrophages is driven by recruitment of BM monocytes, while EMP-derived macrophages proliferate locally and provide a distinct transcriptional response that is linked to tissue regeneration. Our findings thus contribute to the understanding of macrophage heterogeneity, and associate macrophage ontogeny with distinct functions in health and disease.


Asunto(s)
Arterias/citología , Arteritis/inmunología , Diferenciación Celular/fisiología , Homeostasis/fisiología , Macrófagos/fisiología , Envejecimiento/fisiología , Angiotensina II/administración & dosificación , Angiotensina II/inmunología , Animales , Arterias/fisiología , Médula Ósea/fisiología , Trasplante de Médula Ósea , Linaje de la Célula , Modelos Animales de Enfermedad , Femenino , Células Madre Hematopoyéticas/fisiología , Humanos , Masculino , Ratones , Ratones Transgénicos , RNA-Seq , Regeneración/fisiología , Análisis de la Célula Individual , Quimera por Trasplante
17.
Proc Natl Acad Sci U S A ; 117(35): 21469-21479, 2020 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-32817558

RESUMEN

During the postnatal period in mammals, the cardiac muscle transitions from hyperplasic to hypertrophic growth, the extracellular matrix (ECM) undergoes remodeling, and the heart loses regenerative capacity. While ECM maturation and crosstalk between cardiac fibroblasts (CFs) and cardiomyocytes (CMs) have been implicated in neonatal heart development, not much is known about specialized fibroblast heterogeneity and function in the early postnatal period. In order to better understand CF functions in heart maturation and postnatal cardiomyocyte cell-cycle arrest, we have performed gene expression profiling and ablation of postnatal CF populations. Fibroblast lineages expressing Tcf21 or Periostin were traced in transgenic GFP reporter mice, and their biological functions and transitions during the postnatal period were examined in sorted cells using RNA sequencing. Highly proliferative Periostin (Postn)+ lineage CFs were found from postnatal day 1 (P1) to P11 but were not detected at P30, due to a repression of Postn gene expression. This population was less abundant and transcriptionally different from Tcf21+ resident CFs. The specialized Postn+ population preferentially expresses genes related to cell proliferation and neuronal development, while Tcf21+ CFs differentially express genes related to ECM maturation at P7 and immune crosstalk at P30. Ablation of the Postn+ CFs from P0 to P6 led to altered cardiac sympathetic nerve patterning and a reduction in binucleation and hypertrophic growth with increased fetal troponin (TroponinI1) expression in CM. Thus, postnatal CFs are heterogeneous and include a transient proliferative Postn+ population required for cardiac nerve development and cardiomyocyte maturation soon after birth.


Asunto(s)
Diferenciación Celular/genética , Fibroblastos/metabolismo , Miocitos Cardíacos/metabolismo , Animales , Animales Recién Nacidos , Moléculas de Adhesión Celular/metabolismo , Proliferación Celular , Matriz Extracelular , Femenino , Fibroblastos/fisiología , Perfilación de la Expresión Génica/métodos , Regulación del Desarrollo de la Expresión Génica/genética , Hipertrofia/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Miocardio/metabolismo , Análisis de Secuencia de ARN
19.
Circulation ; 141(2): 132-146, 2020 01 14.
Artículo en Inglés | MEDLINE | ID: mdl-31928435

RESUMEN

BACKGROUND: Myxomatous valve degeneration (MVD) involves the progressive thickening and degeneration of the heart valves, leading to valve prolapse, regurgitant blood flow, and impaired cardiac function. Leukocytes composed primarily of macrophages have recently been detected in myxomatous valves, but the timing of the presence and the contributions of these cells in MVD progression are not known. METHODS: We examined MVD progression, macrophages, and the valve microenvironment in the context of Marfan syndrome (MFS) using mitral valves from MFS mice (Fbn1C1039G/+), gene-edited MFS pigs (FBN1Glu433AsnfsX98/+), and patients with MFS. Additional histological and transcriptomic evaluation was performed by using nonsyndromic human and canine myxomatous valves, respectively. Macrophage ontogeny was determined using MFS mice transplanted with mTomato+ bone marrow or MFS mice harboring RFP (red fluorescent protein)-tagged C-C chemokine receptor type 2 (CCR2) monocytes. Mice deficient in recruited macrophages (Fbn1C1039G/+;Ccr2RFP/RFP) were generated to determine the requirements of recruited macrophages to MVD progression. RESULTS: MFS mice recapitulated histopathological features of myxomatous valve disease by 2 months of age, including mitral valve thickening, increased leaflet cellularity, and extracellular matrix abnormalities characterized by proteoglycan accumulation and collagen fragmentation. Diseased mitral valves of MFS mice concurrently exhibited a marked increase of infiltrating (MHCII+, CCR2+) and resident macrophages (CD206+, CCR2-), along with increased chemokine activity and inflammatory extracellular matrix modification. Likewise, mitral valve specimens obtained from gene-edited MFS pigs and human patients with MFS exhibited increased monocytes and macrophages (CD14+, CD64+, CD68+, CD163+) detected by immunofluorescence. In addition, comparative transcriptomic evaluation of both genetic (MFS mice) and acquired forms of MVD (humans and dogs) unveiled a shared upregulated inflammatory response in diseased valves. Remarkably, the deficiency of monocytes was protective against MVD progression, resulting in a significant reduction of MHCII macrophages, minimal leaflet thickening, and preserved mitral valve integrity. CONCLUSIONS: All together, our results suggest sterile inflammation as a novel paradigm to disease progression, and we identify, for the first time, monocytes as a viable candidate for targeted therapy in MVD.


Asunto(s)
Enfermedades de las Válvulas Cardíacas/patología , Síndrome de Marfan/patología , Monocitos/metabolismo , Animales , Quimiocina CCL2/metabolismo , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Perros , Matriz Extracelular/metabolismo , Fibrilina-1/genética , Fibrilina-1/metabolismo , Enfermedades de las Válvulas Cardíacas/complicaciones , Enfermedades de las Válvulas Cardíacas/metabolismo , Antígenos Comunes de Leucocito/metabolismo , Macrófagos/citología , Macrófagos/metabolismo , Síndrome de Marfan/complicaciones , Síndrome de Marfan/metabolismo , Ratones , Ratones Endogámicos C57BL , Válvula Mitral/metabolismo , Válvula Mitral/fisiopatología , Monocitos/citología , Porcinos
20.
Nature ; 577(7790): 405-409, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-31775156

RESUMEN

Clinical trials using adult stem cells to regenerate damaged heart tissue continue to this day1,2, despite ongoing questions of efficacy and a lack of mechanistic understanding of the underlying biological effect3. The rationale for these cell therapy trials is derived from animal studies that show a modest but reproducible improvement in cardiac function in models of cardiac ischaemic injury4,5. Here we examine the mechanistic basis for cell therapy in mice after ischaemia-reperfusion injury, and find that-although heart function is enhanced-it is not associated with the production of new cardiomyocytes. Cell therapy improved heart function through an acute sterile immune response characterized by the temporal and regional induction of CCR2+ and CX3CR1+ macrophages. Intracardiac injection of two distinct types of adult stem cells, cells killed by freezing and thawing or a chemical inducer of the innate immune response all induced a similar regional accumulation of CCR2+ and CX3CR1+ macrophages, and provided functional rejuvenation to the heart after ischaemia-reperfusion injury. This selective macrophage response altered the activity of cardiac fibroblasts, reduced the extracellular matrix content in the border zone and enhanced the mechanical properties of the injured area. The functional benefit of cardiac cell therapy is thus due to an acute inflammatory-based wound-healing response that rejuvenates the infarcted area of the heart.


Asunto(s)
Inmunidad Innata , Miocitos Cardíacos/inmunología , Trasplante de Células Madre , Células Madre , Animales , Diferenciación Celular , Femenino , Macrófagos/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , Miocitos Cardíacos/trasplante , Rejuvenecimiento
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