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Cardiovascular diseases remain the leading cause of death worldwide, with pathological fibrotic remodeling mediated by activated cardiac myofibroblasts representing a unifying theme across etiologies. Despite the profound contributions of myocardial fibrosis to cardiac dysfunction and heart failure, there currently exist limited clinical interventions that effectively target the cardiac fibroblast and its role in fibrotic tissue deposition. Exploration of novel strategies designed to mitigate or reverse myofibroblast activation and cardiac fibrosis will likely yield powerful therapeutic approaches for the treatment of multiple diseases of the heart, including heart failure with preserved or reduced ejection fraction, acute coronary syndrome, and cardiovascular disease linked to type 2 diabetes. In this Review, we provide an overview of classical regulators of cardiac fibrosis and highlight emerging, next-generation epigenetic regulatory targets that have the potential to revolutionize treatment of the expanding cardiovascular disease patient population.

In diseased organs, stress-activated signalling cascades alter chromatin, thereby triggering maladaptive cell state transitions. Fibroblast activation is a common stress response in tissues that worsens lung, liver, kidney and heart disease, yet its mechanistic basis remains unclear 1 , 2 . Pharmacological inhibition of bromodomain and extra-terminal domain (BET) proteins alleviates cardiac dysfunction 3 – 7 , providing a tool to interrogate and modulate cardiac cell states as a potential therapeutic approach. Here we use single-cell epigenomic analyses of hearts dynamically exposed to BET inhibitors to reveal a reversible transcriptional switch that underlies the activation of fibroblasts. Resident cardiac fibroblasts demonstrated robust toggling between the quiescent and activated state in a manner directly correlating with BET inhibitor exposure and cardiac function. Single-cell chromatin accessibility revealed previously undescribed DNA elements, the accessibility of which dynamically correlated with cardiac performance. Among the most dynamic elements was an enhancer that regulated the transcription factor MEOX1, which was specifically expressed in activated fibroblasts, occupied putative regulatory elements of a broad fibrotic gene program and was required for TGFβ-induced fibroblast activation. Selective CRISPR inhibition of the single most dynamic cis -element within the enhancer blocked TGFβ-induced Meox1 activation. We identify MEOX1 as a central regulator of fibroblast activation associated with cardiac dysfunction and demonstrate its upregulation after activation of human lung, liver and kidney fibroblasts. The plasticity and specificity of BET-dependent regulation of MEOX1 in tissue fibroblasts provide previously unknown trans - and cis -targets for treating fibrotic disease. BET proteins regulate a reversible transcriptional switch that governs fibroblast activation in heart disease through the transcription factor MEOX1.

Passive stiffness of the heart is determined largely by extracellular matrix and titin, which functions as a molecular spring within sarcomeres. Titin stiffening is associated with the development of diastolic dysfunction (DD), while augmented titin compliance appears to impair systolic performance in dilated cardiomyopathy. We found that myofibril stiffness was elevated in mice lacking histone deacetylase 6 (HDAC6). Cultured adult murine ventricular myocytes treated with a selective HDAC6 inhibitor also exhibited increased myofibril stiffness. Conversely, HDAC6 overexpression in cardiomyocytes led to decreased myofibril stiffness, as did ex vivo treatment of mouse, rat, and human myofibrils with recombinant HDAC6. Modulation of myofibril stiffness by HDAC6 was dependent on 282 amino acids encompassing a portion of the PEVK element of titin. HDAC6 colocalized with Z-disks, and proteomics analysis suggested that HDAC6 functions as a sarcomeric protein deacetylase. Finally, increased myofibril stiffness in HDAC6-deficient mice was associated with exacerbated DD in response to hypertension or aging. These findings define a role for a deacetylase in the control of myofibril function and myocardial passive stiffness, suggest that reversible acetylation alters titin compliance, and reveal the potential of targeting HDAC6 to manipulate the elastic properties of the heart to treat cardiac diseases.

Chronic inflammation and tissue fibrosis are common responses that worsen organ function, yet the molecular mechanisms governing their cross-talk are poorly understood. In diseased organs, stress-induced gene expression changes fuel maladaptive cell state transitions 1 and pathological interaction between cellular compartments. Although chronic fibroblast activation worsens dysfunction in the lungs, liver, kidneys and heart, and exacerbates many cancers 2 , the stress-sensing mechanisms initiating transcriptional activation of fibroblasts are poorly understood. Here we show that conditional deletion of the transcriptional co-activator Brd4 in infiltrating Cx3cr1 + macrophages ameliorates heart failure in mice and significantly reduces fibroblast activation. Analysis of single-cell chromatin accessibility and BRD4 occupancy in vivo in Cx3cr1 + cells identified a large enhancer proximal to interleukin-1β (IL-1β, encoded by Il1b ), and a series of CRISPR-based deletions revealed the precise stress-dependent regulatory element that controls Il1b expression. Secreted IL-1β activated a fibroblast RELA-dependent (also known as p65) enhancer near the transcription factor MEOX1 , resulting in a profibrotic response in human cardiac fibroblasts. In vivo, antibody-mediated IL-1β neutralization improved cardiac function and tissue fibrosis in heart failure. Systemic IL-1β inhibition or targeted Il1b deletion in Cx3cr1 + cells prevented stress-induced Meox1 expression and fibroblast activation. The elucidation of BRD4-dependent cross-talk between a specific immune cell subset and fibroblasts through IL-1β reveals how inflammation drives profibrotic cell states and supports strategies that modulate this process in heart disease and other chronic inflammatory disorders featuring tissue remodelling. Conditional deletion of the transcriptional co-activator Brd4 in infiltrating Cx3cr1 + mouse macrophages ameliorates heart failure and substantially reduces fibroblast activation.

Class IIa histone deacetylases (HDACs) repress cardiomyocyte hypertrophy through association with the prohypertrophic transcription factor (TF) myocyte enhancer factor-2 (MEF2). The four class IIa HDACs - HDAC4, -5, -7, and -9 - are subject to signal-dependent phosphorylation by members of the Ca2+/calmodulin-dependent protein kinase (CaMK) group. In response to stress, HDAC4, HDAC5, and HDAC9 undergo phosphorylation-induced nuclear export in cardiomyocytes, freeing MEF2 to stimulate progrowth genes; it was generally assumed that HDAC7 is also antihypertrophic. However, in this issue of the JCI, Hsu and colleagues demonstrate that, in sharp contrast to the other class IIa HDACs, HDAC7 is constitutively localized to the cardiomyocyte cytoplasm, where it promotes cardiac hypertrophy. Phosphorylation of HDAC7 by the CaMK group member salt-inducible kinase 1 (SIK1) stabilized the deacetylase, leading to increased expression of c-Myc, which in turn stimulated a pathological gene program. These unexpected findings highlight the SIK1/HDAC7 signaling axis as a promising target for the treatment of cardiac hypertrophy and heart failure.

A study in Nature Metabolism reveals a hitherto-unknown enzymatic and physiological role of ABHD5, which acts as a protease that couples extracellular cues to the epigenome of cardiomyocytes by cleaving histone deacetylase 4 (HDAC4).

The half-life of proteins is tightly regulated and underlies many cellular processes. It remains unclear the extent to which proteins are dynamically synthesized and degraded in different cell types and cell states. We introduce an improved D O labeling workflow and apply it to examine the landscape of protein turnover in pluripotent and differentiating human induced pluripotent stem cells (hiPSC). The majority of hiPSC proteins show minimal turnover beyond cell doubling rates, but we also identify over 100 new fast-turnover proteins not previously described as short-lived. These include proteins that function in cell division and cell cycle checkpoints, that are enriched in APC/C and SPOP degrons, and that are depleted upon pluripotency exit. Differentiation rapidly shifts the set of fast-turnover proteins toward including RNA binding and splicing proteins. The ability to identify fast-turnover proteins in different cell cultures also facilitates secretome analysis, as exemplified by studies of hiPSC-derived cardiac myocytes and primary human cardiac fibroblasts. The presented workflow is broadly applicable to protein turnover studies in diverse primary, pluripotent, and transformed cells.

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 in -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 -positive cells identified a large enhancer proximal to ( , and a series of CRISPR deletions revealed the precise stress-dependent regulatory element that controlled expression of in disease. Secreted IL1B functioned non-cell autonomously to activate a p65/RELA-dependent enhancer near the transcription factor , resulting in a profibrotic response in human cardiac fibroblasts. , antibody-mediated IL1B neutralization prevented stress-induced expression of , 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.

Cardiomyocyte hypertrophy is a key clinical predictor of heart failure. High-throughput and AI-driven screens have potential to identify drugs and downstream pathways that modulate cardiomyocyte hypertrophy. Here we developed LogiRx, a logic-based mechanistic machine learning method that predicts drug-induced pathways. We applied LogiRx to discover how drugs discovered in a previous compound screen attenuate cardiomyocyte hypertrophy. We experimentally validated LogiRx predictions in neonatal cardiomyocytes, adult mice, and two patient databases. Using LogiRx, we predicted anti-hypertrophic pathways for 7 drugs currently used to treat non-cardiac disease. We experimentally validated that escitalopram (Lexapro) and mifepristone inhibit hypertrophy of cultured cardiomyocytes in two contexts. The LogiRx model predicted that escitalopram prevents hypertrophy through an off-target serotonin receptor/PI3Kgamma; pathway, mechanistically validated using additional investigational drugs. Further, escitalopram reduced cardiomyocyte hypertrophy in a mouse model of hypertrophy and fibrosis. Finally, mining of both FDA and University of Virginia databases showed that patients with depression on escitalopram have a lower incidence of cardiac hypertrophy than those prescribed other serotonin reuptake inhibitors that do not target the serotonin receptor. Mechanistic machine learning by LogiRx discovers drug pathways that perturb cell states, which may enable repurposing of escitalopram and other drugs to limit cardiac remodeling through off-target pathways.Competing Interest StatementThe authors have declared no competing interest.Footnotes* Revised text to address reviewer comments. Added new supplemental figures/table.

Heart failure, the final clinical manifestation of numerous cardiovascular maladies, is a devastating disease characterized by interstitial fibrosis, chamber remodeling and reduced ventricular compliance. Elevated myocardial sympathetic stimulation, a hallmark of heart failure, induces pathological signaling through G protein βγ subunits that results in the activation and membrane recruitment of G protein-coupled receptor kinase 2 (GRK2). In the failing heart, diminished cardiac output triggers a vicious cycle of persistent sympathetic stimulation accompanied by perpetual maladaptive signaling due in large part to GRK2-mediated β-adrenergic receptor desensitization and loss of responsiveness. We recently identified and validated the novel small molecule inhibitor gallein that disrupts the Gβγ-GRK2 interaction. Here, we investigated the therapeutic potential of gallein in murine ischemia-reperfusion (I/R) injury, a clinically relevant model of ischemic heart failure. We found that pharmacological disruption of Gβγ-GRK2 signaling post-I/R offered significant protection against cardiac dysfunction and remodeling. Moreover, we observed that gallein treatment significantly ameliorated fibrotic infarct expansion and the expression of several pro-fibrotic markers, which likely contributed to the overall improvement in ventricular contractility. One principal objective was to decipher the cellular specificity of gallein by ablating GRK2 in various resident cell populations of the heart. While the salutary properties of cardiomyocyte-specific ablation of GRK2 have been extensively documented, our goal was to explore the potential cardiomyocyte-independent cardioprotective properties of gallein. While GRK2 ablation in cardiomyocytes offered modest protection against cardiac dysfunction and remodeling, it was only with concurrent gallein treatment that significant cardioprotection was achieved. These findings suggested functional significance for Gβγ-GRK2 inhibition in cell types beyond the cardiomyocyte. Cardiac fibroblasts are an essential cell population responsible for myocardial extracellular matrix homeostasis, however upon injury or pathological stimulation, these cells transform into activated myofibroblasts and play a fundamental role in myocardial fibrosis and remodeling. In this dissertation, we present evidence that gallein treatment reduces prototypical activation characteristics of cultured mouse cardiac fibroblasts, as well as human cardiac myofibroblasts isolated from patients with end-stage heart failure. We also demonstrate that pharmacological inhibition of Gβγ-GRK2 restores physiologic adrenergic receptor signaling in activated murine and human cardiac myofibroblasts. These discoveries warranted our exploration of the therapeutic potential of inducible ablation of GRK2 in activated cardiac fibroblasts after ischemic cardiac injury. Remarkably, mice with myofibroblast-specific deletion of GRK2 exhibited nearly complete preservation of cardiac function and significantly reduced fibrotic scar expansion post-I/R. As an unexpected consequence, concurrent gallein administration offered little to no further improvements to cardiac function or remodeling. These findings suggested the cardioprotective properties of gallein were significantly mediated through its effects in the activated cardiac myofibroblast. The results presented herein reveal the cardioprotective properties of pharmacological and activated fibroblast-specific targeting of the Gβγ-GRK2 interface in limiting pathologic myofibroblast activation, interstitial fibrosis and heart failure progression after ischemic myocardial insult. This work contributes further evidence to the beneficial effects of Gβγ-GRK2 inhibition, and offers significant potential to culminate in the development of direly needed novel therapeutic strategies for the treatment of heart failure.