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Background:
Cardiac fibroblasts are a critical cell population responsible for myocardial extracellular matrix homeostasis. Upon injury or pathological stimulation, these cells transform to an activated myofibroblast state and play a fundamental role in myocardial fibrosis and remodeling. Chronic sympathetic overstimulation, a hallmark of heart fa...
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... of the cardioprotective attributes of small molecule G??-GRK2 inhibition was assessed in animals possessing the GRK2 fl/fl allele, as these mice would serve as controls for subsequent genetic ablation studies when crossed with various Cre lines. Gallein treatment was initiated 1 week post-injury as described to investigate its therapeutic efficacy in treating extant HF ( Figure 1A). Animals receiving vehicle demonstrated significant deterioration in overall cardiac function 4 weeks post-I/R. Remarkably, mice treated with gallein initiated 1 week post-I/R exhibited significant preservation of contractile performance and ventricular volumes ( Figure 1B) as measured by percent fractional shortening ( Figure 1C), ejection fraction ( Figure 1D), and left ventricular (LV) volume ( Figure 1E). Echocardiographic strain analysis supported this finding, revealing significant restoration in peak wall contraction in animals receiving gallein, indicating attenuation of progressive LV dysfunction ( Figure 1F). Subsequent qPCR analysis of injured mice receiving gallein post-I/R demonstrated a significant reduction in the messenger ribonucleic acid (mRNA) levels of natriuretic peptide B (Nppb) (Figure 1G), ?-myosin heavy chain (Myh7) ( Figure 1H) and natriuretic peptide A (Nppa) (Online Figure 2A) in comparison to vehicle-treated control ...
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... observed preservation of cardiac function by post-I/R gallein treatment occurred commensurate with an overall reduction in post-I/R fibrosis, particularly with regard to infarct expansion. Serial cardiac longitudinal sections were stained by picrosirius red to determine the extent of collagen deposition following injury ( Figure 2A). Fibrosis was quantified in relation to total LV area, revealing a significant reduction in pathological fibrotic expansion from the initial infarct region in gallein-treated mice ( Figure 2B). Immunofluorescence revealed a parallel reduction in the presence of periostin, which is produced specifically by activated fibroblasts following tissue injury (12), in gallein-treated mice compared with vehicle controls ( Figure 2C). Furthermore, gene expression analysis revealed a concomitant reduction in the transcript expression of collagen type I ?1 (col1?1) ( Figure 2D), periostin (Postn) ( Figure 2E), and fibronectin 1 (Fn1) (Online Figure 2C), along with trends toward a decrease in the expression of collagen type III ?1 (Col3?1) (Online Figure 2B) in mice treated with gallein. Overall, pharmacological G??-GRK2 inhibition initiated post-I/R provided functional protection and reduced post-I/R infarct expansion following ischemic myocardial ...
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... observed preservation of cardiac function by post-I/R gallein treatment occurred commensurate with an overall reduction in post-I/R fibrosis, particularly with regard to infarct expansion. Serial cardiac longitudinal sections were stained by picrosirius red to determine the extent of collagen deposition following injury ( Figure 2A). Fibrosis was quantified in relation to total LV area, revealing a significant reduction in pathological fibrotic expansion from the initial infarct region in gallein-treated mice ( Figure 2B). Immunofluorescence revealed a parallel reduction in the presence of periostin, which is produced specifically by activated fibroblasts following tissue injury (12), in gallein-treated mice compared with vehicle controls ( Figure 2C). Furthermore, gene expression analysis revealed a concomitant reduction in the transcript expression of collagen type I ?1 (col1?1) ( Figure 2D), periostin (Postn) ( Figure 2E), and fibronectin 1 (Fn1) (Online Figure 2C), along with trends toward a decrease in the expression of collagen type III ?1 (Col3?1) (Online Figure 2B) in mice treated with gallein. Overall, pharmacological G??-GRK2 inhibition initiated post-I/R provided functional protection and reduced post-I/R infarct expansion following ischemic myocardial ...
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... observed preservation of cardiac function by post-I/R gallein treatment occurred commensurate with an overall reduction in post-I/R fibrosis, particularly with regard to infarct expansion. Serial cardiac longitudinal sections were stained by picrosirius red to determine the extent of collagen deposition following injury ( Figure 2A). Fibrosis was quantified in relation to total LV area, revealing a significant reduction in pathological fibrotic expansion from the initial infarct region in gallein-treated mice ( Figure 2B). Immunofluorescence revealed a parallel reduction in the presence of periostin, which is produced specifically by activated fibroblasts following tissue injury (12), in gallein-treated mice compared with vehicle controls ( Figure 2C). Furthermore, gene expression analysis revealed a concomitant reduction in the transcript expression of collagen type I ?1 (col1?1) ( Figure 2D), periostin (Postn) ( Figure 2E), and fibronectin 1 (Fn1) (Online Figure 2C), along with trends toward a decrease in the expression of collagen type III ?1 (Col3?1) (Online Figure 2B) in mice treated with gallein. Overall, pharmacological G??-GRK2 inhibition initiated post-I/R provided functional protection and reduced post-I/R infarct expansion following ischemic myocardial ...
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... observed preservation of cardiac function by post-I/R gallein treatment occurred commensurate with an overall reduction in post-I/R fibrosis, particularly with regard to infarct expansion. Serial cardiac longitudinal sections were stained by picrosirius red to determine the extent of collagen deposition following injury ( Figure 2A). Fibrosis was quantified in relation to total LV area, revealing a significant reduction in pathological fibrotic expansion from the initial infarct region in gallein-treated mice ( Figure 2B). Immunofluorescence revealed a parallel reduction in the presence of periostin, which is produced specifically by activated fibroblasts following tissue injury (12), in gallein-treated mice compared with vehicle controls ( Figure 2C). Furthermore, gene expression analysis revealed a concomitant reduction in the transcript expression of collagen type I ?1 (col1?1) ( Figure 2D), periostin (Postn) ( Figure 2E), and fibronectin 1 (Fn1) (Online Figure 2C), along with trends toward a decrease in the expression of collagen type III ?1 (Col3?1) (Online Figure 2B) in mice treated with gallein. Overall, pharmacological G??-GRK2 inhibition initiated post-I/R provided functional protection and reduced post-I/R infarct expansion following ischemic myocardial ...
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... observed preservation of cardiac function by post-I/R gallein treatment occurred commensurate with an overall reduction in post-I/R fibrosis, particularly with regard to infarct expansion. Serial cardiac longitudinal sections were stained by picrosirius red to determine the extent of collagen deposition following injury ( Figure 2A). Fibrosis was quantified in relation to total LV area, revealing a significant reduction in pathological fibrotic expansion from the initial infarct region in gallein-treated mice ( Figure 2B). Immunofluorescence revealed a parallel reduction in the presence of periostin, which is produced specifically by activated fibroblasts following tissue injury (12), in gallein-treated mice compared with vehicle controls ( Figure 2C). Furthermore, gene expression analysis revealed a concomitant reduction in the transcript expression of collagen type I ?1 (col1?1) ( Figure 2D), periostin (Postn) ( Figure 2E), and fibronectin 1 (Fn1) (Online Figure 2C), along with trends toward a decrease in the expression of collagen type III ?1 (Col3?1) (Online Figure 2B) in mice treated with gallein. Overall, pharmacological G??-GRK2 inhibition initiated post-I/R provided functional protection and reduced post-I/R infarct expansion following ischemic myocardial ...
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... observed preservation of cardiac function by post-I/R gallein treatment occurred commensurate with an overall reduction in post-I/R fibrosis, particularly with regard to infarct expansion. Serial cardiac longitudinal sections were stained by picrosirius red to determine the extent of collagen deposition following injury ( Figure 2A). Fibrosis was quantified in relation to total LV area, revealing a significant reduction in pathological fibrotic expansion from the initial infarct region in gallein-treated mice ( Figure 2B). Immunofluorescence revealed a parallel reduction in the presence of periostin, which is produced specifically by activated fibroblasts following tissue injury (12), in gallein-treated mice compared with vehicle controls ( Figure 2C). Furthermore, gene expression analysis revealed a concomitant reduction in the transcript expression of collagen type I ?1 (col1?1) ( Figure 2D), periostin (Postn) ( Figure 2E), and fibronectin 1 (Fn1) (Online Figure 2C), along with trends toward a decrease in the expression of collagen type III ?1 (Col3?1) (Online Figure 2B) in mice treated with gallein. Overall, pharmacological G??-GRK2 inhibition initiated post-I/R provided functional protection and reduced post-I/R infarct expansion following ischemic myocardial ...
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... observed preservation of cardiac function by post-I/R gallein treatment occurred commensurate with an overall reduction in post-I/R fibrosis, particularly with regard to infarct expansion. Serial cardiac longitudinal sections were stained by picrosirius red to determine the extent of collagen deposition following injury ( Figure 2A). Fibrosis was quantified in relation to total LV area, revealing a significant reduction in pathological fibrotic expansion from the initial infarct region in gallein-treated mice ( Figure 2B). Immunofluorescence revealed a parallel reduction in the presence of periostin, which is produced specifically by activated fibroblasts following tissue injury (12), in gallein-treated mice compared with vehicle controls ( Figure 2C). Furthermore, gene expression analysis revealed a concomitant reduction in the transcript expression of collagen type I ?1 (col1?1) ( Figure 2D), periostin (Postn) ( Figure 2E), and fibronectin 1 (Fn1) (Online Figure 2C), along with trends toward a decrease in the expression of collagen type III ?1 (Col3?1) (Online Figure 2B) in mice treated with gallein. Overall, pharmacological G??-GRK2 inhibition initiated post-I/R provided functional protection and reduced post-I/R infarct expansion following ischemic myocardial ...
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... strain analysis supported this finding, revealing significant restoration in peak wall contraction in animals receiving gallein, indicating attenuation of progressive LV dysfunction ( Figure 1F). Subsequent qPCR analysis of injured mice receiving gallein post-I/R demonstrated a significant reduction in the messenger ribonucleic acid (mRNA) levels of natriuretic peptide B (Nppb) (Figure 1G), β-myosin heavy chain (Myh7) ( Figure 1H) and natriuretic peptide A (Nppa) (Online Figure 2A) in comparison to vehicle-treated control mice. ...
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... observed preservation of cardiac function by post-I/R gallein treatment occurred commensurate with an overall reduction in post-I/R fibrosis, particularly with regard to infarct expansion. Serial cardiac longitudinal sections were stained by picrosirius red to determine the extent of collagen deposition following injury ( Figure 2A). Fibrosis was quantified in relation to total LV area, revealing a significant reduction in pathological fibrotic expansion from the initial infarct region in gallein-treated mice ( Figure 2B). ...
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... cardiac longitudinal sections were stained by picrosirius red to determine the extent of collagen deposition following injury ( Figure 2A). Fibrosis was quantified in relation to total LV area, revealing a significant reduction in pathological fibrotic expansion from the initial infarct region in gallein-treated mice ( Figure 2B). Immunofluorescence revealed a parallel reduction in the presence of periostin, which is produced specifically by activated fibroblasts following tissue injury (12), in gallein-treated mice compared with vehicle controls ( Figure 2C). ...
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... was quantified in relation to total LV area, revealing a significant reduction in pathological fibrotic expansion from the initial infarct region in gallein-treated mice ( Figure 2B). Immunofluorescence revealed a parallel reduction in the presence of periostin, which is produced specifically by activated fibroblasts following tissue injury (12), in gallein-treated mice compared with vehicle controls ( Figure 2C). Furthermore, gene expression analysis revealed a concomitant reduction in the transcript expression of collagen type I α1 (col1α1) ( Figure 2D), periostin (Postn) ( Figure 2E), and fibronectin 1 (Fn1) (Online Figure 2C), along with trends toward a decrease in the expression of collagen type III α1 (Col3α1) (Online Figure 2B) in mice treated with gallein. ...
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... revealed a parallel reduction in the presence of periostin, which is produced specifically by activated fibroblasts following tissue injury (12), in gallein-treated mice compared with vehicle controls ( Figure 2C). Furthermore, gene expression analysis revealed a concomitant reduction in the transcript expression of collagen type I α1 (col1α1) ( Figure 2D), periostin (Postn) ( Figure 2E), and fibronectin 1 (Fn1) (Online Figure 2C), along with trends toward a decrease in the expression of collagen type III α1 (Col3α1) (Online Figure 2B) in mice treated with gallein. Overall, pharmacological Gβγ-GRK2 inhibition initiated post-I/R provided functional protection and reduced post-I/R infarct expansion following ischemic myocardial injury. ...
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... revealed a parallel reduction in the presence of periostin, which is produced specifically by activated fibroblasts following tissue injury (12), in gallein-treated mice compared with vehicle controls ( Figure 2C). Furthermore, gene expression analysis revealed a concomitant reduction in the transcript expression of collagen type I α1 (col1α1) ( Figure 2D), periostin (Postn) ( Figure 2E), and fibronectin 1 (Fn1) (Online Figure 2C), along with trends toward a decrease in the expression of collagen type III α1 (Col3α1) (Online Figure 2B) in mice treated with gallein. Overall, pharmacological Gβγ-GRK2 inhibition initiated post-I/R provided functional protection and reduced post-I/R infarct expansion following ischemic myocardial injury. ...
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... revealed a parallel reduction in the presence of periostin, which is produced specifically by activated fibroblasts following tissue injury (12), in gallein-treated mice compared with vehicle controls ( Figure 2C). Furthermore, gene expression analysis revealed a concomitant reduction in the transcript expression of collagen type I α1 (col1α1) ( Figure 2D), periostin (Postn) ( Figure 2E), and fibronectin 1 (Fn1) (Online Figure 2C), along with trends toward a decrease in the expression of collagen type III α1 (Col3α1) (Online Figure 2B) in mice treated with gallein. Overall, pharmacological Gβγ-GRK2 inhibition initiated post-I/R provided functional protection and reduced post-I/R infarct expansion following ischemic myocardial injury. ...
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... revealed a parallel reduction in the presence of periostin, which is produced specifically by activated fibroblasts following tissue injury (12), in gallein-treated mice compared with vehicle controls ( Figure 2C). Furthermore, gene expression analysis revealed a concomitant reduction in the transcript expression of collagen type I α1 (col1α1) ( Figure 2D), periostin (Postn) ( Figure 2E), and fibronectin 1 (Fn1) (Online Figure 2C), along with trends toward a decrease in the expression of collagen type III α1 (Col3α1) (Online Figure 2B) in mice treated with gallein. Overall, pharmacological Gβγ-GRK2 inhibition initiated post-I/R provided functional protection and reduced post-I/R infarct expansion following ischemic myocardial injury. ...
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Citations
... This increase in CRK2 expression may be attributed to the sustained activation of cardiac β-adrenergic receptors [28]. Inhibition of GRK2 can attenuate hypertrophic and fibrotic responses in cardiomyocytes [38,39]. Previous studies have reported that paroxetine has beneficial effects against pathological cardiac hypertrophy and fibrosis, compared to other existing SSRIs, because it acts as a GRK2 inhibitor [28,29,40]. ...
Pathological cardiac remodeling is associated with cardiovascular disease and can lead to heart failure. Nuclear factor-kappa B (NF-κB) is upregulated in the hypertrophic heart. Moreover, the expression of the G-protein-coupled receptor kinase 2 (GRK2) is increased and linked to the progression of heart failure. The inhibitory effects of paroxetine on GRK2 have been established. However, its protective effect on IκBα/NFκB signaling has not been elucidated. This study investigated the cardioprotective effect of paroxetine in an animal model of cardiac hypertrophy (CH), focusing on its effect on GRK2-mediated NF-κB-regulated expression of prohypertrophic and profibrotic genes. Wistar albino rats were administered normal saline, paroxetine, or fluoxetine, followed by isoproterenol to induce CH. The cardioprotective effects of the treatments were determined by assessing cardiac injury, inflammatory biomarker levels, histopathological changes, and hypertrophic and fibrotic genes in cardiomyocytes. Paroxetine pre-treatment significantly decreased the HW/BW ratio (p < 0.001), and the expression of prohypertrophic and profibrotic genes Troponin-I (p < 0.001), BNP (p < 0.01), ANP (p < 0.001), hydroxyproline (p < 0.05), TGF-β1 (p < 0.05), and αSMA (p < 0.01) as well as inflammatory markers. It also markedly decreased pIκBα, NFκB(p105) subunit expression (p < 0.05) and phosphorylation. The findings suggest that paroxetine prevents pathological cardiac remodeling by inhibiting the GRK2-mediated IκBα/NF-κB signaling pathway.
... Other antifibrotic interventions have focused on the enhancement of the β2-AR signalling pathway via inhibiting the G proteincoupled receptor kinase 2 (GRK2), which phosphorylates the receptor leading to its desensitization. Different works [35][36][37] have also described that the fibroblast-specific inhibition of GRK2 could prevent cardiac fibrosis and dysfunction in animal models of heart failure. Nonetheless, β2-ARs have been shown to increase DNA synthesis, proliferation, and production of pro-fibrotic interleukin 6 (IL-6) in isolated rat and human CFs [38][39][40]. ...
Cardiovascular diseases are the first cause of death worldwide, with a heavy social and economic impact. They include a wide range of pathological conditions, among which cardiac fibrosis represents a common pathogenetic hallmark. The fibrotic process is driven by cardiac mesenchymal stromal cells, namely fibroblasts, which become activated, proliferate, and differentiate into myofibroblasts in response to several stimuli, in the end secreting extracellular matrix proteins, and mediating cardiac tissue remodelling and stiffening. A specific therapy for the exclusive treatment of cardiac fibrosis is still lacking. Given the growing quest for reducing the burden of cardiovascular diseases, there is increasing interest in the search for new effective anti-fibrotic therapies. In this review, we will briefly summarize the limited pharmacological therapies known to act, at least in part, against cardiac fibrosis. Then we will present novel potential active molecules, molecular targets, and biotechnological approaches emerged in the last decade, as possible future therapeutic strategies for cardiac fibrosis, with a specific focus on targeting fibroblast activation and function.
... Furthermore, we have detected Gβ 1 occupancy at numerous gene promoters in human embryonic kidney 293 (HEK 293) cells (23). While canonical Gβγ signaling has been implicated in both cardiac fibrosis and heart failure (24,25), how nuclear Gβγ signaling impacts these events is currently unknown. ...
Gβγ subunits mediate many different signaling processes in various compartments of the cell, including the nucleus. To gain insight into the functions of nuclear Gβγ signaling, we investigated the functional role of Gβγ signaling in the regulation of GPCR-mediated gene expression in primary rat neonatal cardiac fibroblasts. We identified a novel, negative, regulatory role for the Gβ1γ dimer in the fibrotic response. Depletion of Gβ1 led to de-repression of the fibrotic response at the mRNA and protein levels under basal conditions and an enhanced fibrotic response after sustained stimulation of the angiotensin II type I receptor. Our genome-wide chromatin immunoprecipitation experiments revealed that Gβ1 co-localized and interacted with RNA polymerase II on fibrotic genes in an angiotensin II-dependent manner. Additionally, blocking transcription with inhibitors of Cdk9 prevented association of Gβγ with transcription complexes. Together, our findings suggest that Gβ1γ is a novel transcriptional regulator of the fibrotic response that may act to restrict fibrosis to conditions of sustained fibrotic signaling. Our work expands the role for Gβγ signaling in cardiac fibrosis and may have broad implications for the role of nuclear Gβγ signaling in other cell types.
... Under chronic stimulation, adrenergic receptors are desensitized by a mechanism that involves G-protein-coupled kinase (GRK) and βarrestin. In HF patients, GRK2 is elevated and has been proposed to counteract cardiac fibrosis [95,96]. ...
Cardiac fibrosis constitutes irreversible necrosis of the heart muscle as a consequence of different acute (myocardial infarction) or chronic (diabetes, hypertension, …) diseases but also due to genetic alterations or aging. Currently, there is no curative treatment that is able to prevent or attenuate this phenomenon that leads to progressive cardiac dysfunction and life-threatening outcomes. This review summarizes the different targets identified and the new strategies proposed to fight cardiac fibrosis. Future directions, including the use of exosomes or nanoparticles, will also be discussed.
... The relationship between Wnt pathway and CHD was further assessed by the GSEA on the array data obtained with epicardial and subcutaneous adipose tissue in CHD patients (GSE120774 in GEO) 34 . Similar to our mouse model, the GSEA results show Wnt pathway is also significantly activated in CHD patients ( Fig. S3B and S3C). ...
Heart failure is the leading cause of death worldwide. Compound Danshen Dripping Pill (CDDP) or CDDP combined with simvastatin has been widely used to treat patients with myocardial infarction and other cardiovascular diseases in China. However, the effect of CDDP on hypercholesterolemia/atherosclerosis-induced heart failure is unknown. We constructed a new model of heart failure induced by hypercholesterolemia/atherosclerosis in ApoE and LDLR receptor (LDLR) dual deficient (ApoE–/–LDLR–/–) mice and investigated the effect of CDDP or CDDP plus a low dose of simvastatin on the heart failure. CDDP or CDDP plus a low dose of simvastatin inhibited heart injury by multiple actions including anti-myocardial dysfunction and anti-fibrosis. Mechanistically, both Wnt and lysine-specific demethylase 4A (KDM4A) pathways were significantly activated in mice with heart injury. Conversely, CDDP or CDDP plus a low dose of simvastatin inhibited Wnt pathway by markedly up-regulating expression of Wnt inhibitors. While the anti-inflammation and anti-oxidative stress by CDDP were achieved by inhibiting KDM4A expression and activity. In addition, CDDP attenuated simvastatin-induced myolysis in skeletal muscle. Taken together, our study suggests that CDDP or CDDP plus a low dose of simvastatin can be an effective therapy to reduce hypercholesterolemia/atherosclerosis-induced heart failure.
... Moreover, a small molecule Gβγ inhibitor Gallein has been shown to inhibit myofibroblast activation in vitro (77). Gallein treatment a week after ischemic/reperfusion is effective in reducing cardiac fibrosis and preserving ejection fraction in a mouse model of chronic heart failure (29). Since GPCRs are comprised of α and βγ subunits, differentiating the effects of Gas (i.e., antifibrotic) from that of Gβγ (i.e., fibrotic) is challenging and may depend on factors such as cell type of receptor expression. ...
Cardiac fibrosis occurs ubiquitously in ischemic heart failure, genetic cardiomyopathies, diabetes mellitus, and aging. It triggers myocardial stiffness, which impairs cardiac function, ultimately progressing to end-stage heart failure and increased mortality. Although several targets for anti-fibrotic therapies have been identified, including TGF-β and receptor tyrosine kinase, there is currently no FDA-approved drug specifically targeting cardiac fibrosis. G protein-coupled receptors (GPCRs) are integral, multipass membrane-bound receptors that exhibit diverse and cell-specific expression, offering novel and unrealized therapeutic targets for cardiac fibrosis. This review highlights the emerging roles of several GPCRs and briefly explores their downstream pathways that are crucial in cardiac fibrosis. We will not only provide an overview of the GPCRs expressed on cardiac fibroblasts that are directly involved in myofibroblast activation but also describe those GPCRs which contribute to cardiac fibrosis via indirect crosstalk mechanisms. We also discuss the challenges of identifying novel effective therapies for cardiac fibrosis and offer strategies to circumvent these challenges.
... When chimeric antigen receptor-T cells were used to specifically target an endogenous cell-surface glycoprotein on activated fibroblasts, fibrosis was reduced, leading to better cardiac function (Aghajanian et al., 2019). Similarly, ablation of activated fibroblasts (Kaur et al., 2016) or activated fibroblast-specific depletion of Grk2, a downstream effector of G protein-coupled receptors known to be elevated in patients with heart failure (Travers et al., 2017), was shown to be cardioprotective following injury. While these studies suggest beneficial outcomes from fibroblast reduction, others have observed increased lethality and ventricular wall rupture, presumably due to reduced ECM deposition (Kanisicak et al., 2016;Molkentin et al., 2017). ...
... However, studies that have focused on specifically reducing activated fibroblasts or targeting genes in activated fibroblasts to attenuate pathological fibrosis have produced conflicting results. In some circumstances, fibroblast disruption leads to rupture while in other scenarios manipulations of fibroblasts appear to be protective (Kanisicak et al., 2016;Khalil et al., 2019;Molkentin et al., 2017;Kaur et al., 2016;Aghajanian et al., 2019;Travers et al., 2017;Kretzschmar et al., 2018;Maruyama et al., 2016;Kong et al., 2018). Our work further demonstrates that resident fibroblast reduction prior to injury may have beneficial outcomes under certain pathological conditions. ...
Fibroblasts produce the majority of collagen in the heart and are thought to regulate extracellular matrix (ECM) turnover. Although fibrosis accompanies many cardiac pathologies and is generally deleterious, the role of fibroblasts in maintaining the basal ECM network and in fibrosis in vivo is poorly understood. We genetically ablated fibroblasts in mice to evaluate the impact on homeostasis of adult ECM and cardiac function after injury. Fibroblast-ablated mice demonstrated a substantive reduction in cardiac fibroblasts, but fibrillar collagen and the ECM proteome were not overtly altered when evaluated by quantitative mass spectrometry and N-terminomics. However, the distribution and quantity of collagen VI, a microfibrillar collagen that forms an open network with the basement membrane, was reduced. In fibroblast-ablated mice, cardiac function was better preserved following angiotensin II/phenylephrine (AngII/PE)-induced fibrosis and myocardial infarction (MI). Analysis of cardiomyocyte function demonstrated altered sarcomere shortening and slowed calcium decline in both uninjured and AngII/PE infused fibroblast-ablated mice. After MI, the residual resident fibroblasts responded to injury, albeit with reduced proliferation and numbers immediately after injury. These results indicate that the adult mouse heart tolerates a significant degree of fibroblast loss with potentially beneficial impact on cardiac function after injury. The cardioprotective effect of controlled fibroblast reduction may have therapeutic value in heart disease.
... A recent study explored cardiac fibroblast GRK2 deletion enhances contractility and remodeling following ischemia/reperfusion injury [20]. Given that the positive feedback loop of TGF-β1-GRK2 in cardiomyocytes contributes to cardiac hypertrophy (Figs. 4 and 5), we hypothesized that GRK2 may be a potential non-canonical TGF-β1 target in cardiac fibroblasts. ...
Inflammation plays a central role in the development of heart failure. Prostaglandin E2 (PGE2) is a key mediator of the inflammatory process in the cardiovascular system. However, the role of PGE2 in heart failure is complex and controversial. A recent report suggested that PGE2 inhibits acute β adrenergic receptor (β-AR) stimulation-enhanced cardiac contractility. The aim of this study was to characterize the influence of PGE2 on chronic β-AR stimulation-induced heart failure. Male C57BL/6 J mice received isoproterenol (ISO) or vehicle for 4 weeks. PGE2 significantly reversed ISO-induced cardiac contractile dysfunction and remodeling. Mechanically, ventricular myocytes were found to be an important source of TGF-β1 in ISO-model and PGE2 ablated TGF-β1 synthesis in cardiomyocytes through inhibition of β-AR activated PKA-CREB signaling. Furthermore, PGE2 significantly suppressed TGF-β1-GRK2 crosstalk-induced pro-hypertrophy and pro-fibrotic signaling in cardiomyocytes and cardiac fibroblasts, respectively. Pharmacological inhibition of GRK2 also attenuated contractile dysfunction and cardiac hypertrophy and fibrosis in ISO-model. These studies elucidate a novel mechanism by which PGE2 reduces TGF-β1 synthesis and its downstream signaling in heart failure and identify PGE2 or TGF-β1-GRK2 crosstalk as plausible therapeutic targets for preventing or treating heart failure induced by chronic β-AR stimulation.
... Recent studies have also demonstrated the role of compound 19 in chronic degenerative diseases. Furthermore, compound 19 could switch the phenotypic reprogramming from M1 to M2 phenotype in a rat model of EAM heart and human macrophages [148], directly alleviating myocardial and renal dysfunction and fibrosis [149]. These findings suggest the potential of 18 and 19 to be involved in HF pharmacological therapies. ...
The development of small-molecule inhibitors targeting G protein-coupled receptor kinase 2 (GRK2) and G protein-coupled receptor kinase 5 (GRK5) for the treatment of chronic degenerative diseases has attracted wide attention. GRK2 and GRK5 can regulate essential physiological processes by phosphorylating G protein-coupled receptor (GPCR). Alterations in the functional levels of GRK2 and GRK5 have been found in a variety of chronic degenerative diseases, such as cardiovascular diseases, neurodegenerative diseases, cancers, type 2 diabetes, and rheumatoid arthritis (RA). Abnormal GRK2 and GRK5 expression contribute to the development of chronic degenerative diseases through environmental molecular mechanisms, making them promising molecular targets for treating chronic degenerative diseases. To date, many novel GRK2 and GRK5 inhibitors have been reported for the treatment of chronic degenerative diseases. We focuses on the recent progress of single and dual-target inhibitors of GRK2/GRK5. It summarizes the structural optimization rationale, structure-activity relationships (SARs), and the latest application in the treatment of chronic degenerative diseases. This review should shed light on the future development of small molecule inhibitors of GRK2 and GRK5, as well as the clinical applications in chronic degenerative diseases.
... Moreover, G βγ -GRK2 inhibition reduces pathological effect of myofibroblast activation. Thus, G βγ -GRK2 inhibition might be a potential therapeutic strategy to attenuate pathological myofibroblast activation, interstitial fibrosis, cardiac remodeling, and progression of heart failure [76]. ...
G protein-coupled receptor kinases (GRKs), the negative regulators of G protein-coupled receptors (GPCRs), have a key role in cardiovascular disease pathophysiology. Alteration in GRKs’ expressions and/or kinase activity has been reported in preclinical animal models as well as in patients with cardiovascular diseases. This alteration might be a contributing factor to disease progression by a variety of mechanisms such as non-canonical transduction pathways. The current chapter is aimed to expand our knowledge and understanding of the function of GRKs in cardiovascular diseases, highlight their involvement, and illustrate the possible mechanistic role of GRKs in hypertensive vascular diseases and cardiac myopathy. The current chapter also is endeavoured to identify the potential molecular mechanisms by which GRKs participate in cardiovascular disease progression. Building the basics knowledge about GRKs in cardiovascular diseases will help to assess the potential utilization of GRKs as therapeutic targets and to examine the possible approaches to modulate their protein expression or to inhibit their kinase activity to prevent or attenuate cardiovascular disease progression.
