JAK/STAT3 signaling in cardiac fibrosis: a promising therapeutic target.

Cardiac fibrosis is a serious health problem because it is a common pathological change in almost all forms of cardiovascular diseases. Cardiac fibrosis is characterized by the transdifferentiation of cardiac fibroblasts (CFs) into cardiac myofibroblasts and the excessive deposition of extracellular matrix (ECM) components produced by activated myofibroblasts, which leads to fibrotic scar formation and subsequent cardiac dysfunction. However, there are currently few effective therapeutic strategies protecting against fibrogenesis. This lack is largely because the molecular mechanisms of cardiac fibrosis remain unclear despite extensive research. The Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling cascade is an extensively present intracellular signal transduction pathway and can regulate a wide range of biological processes, including cell proliferation, migration, differentiation, apoptosis, and immune response. Various upstream mediators such as cytokines, growth factors and hormones can initiate signal transmission via this pathway and play corresponding regulatory roles. STAT3 is a crucial player of the JAK/STAT pathway and its activation is related to inflammation, malignant tumors and autoimmune illnesses. Recently, the JAK/STAT3 signaling has been in the spotlight for its role in the occurrence and development of cardiac fibrosis and its activation can promote the proliferation and activation of CFs and the production of ECM proteins, thus leading to cardiac fibrosis. In this manuscript, we discuss the structure, transactivation and regulation of the JAK/STAT3 signaling pathway and review recent progress on the role of this pathway in cardiac fibrosis. Moreover, we summarize the current challenges and opportunities of targeting the JAK/STAT3 signaling for the treatment of fibrosis. In summary, the information presented in this article is critical for comprehending the role of the JAK/STAT3 pathway in cardiac fibrosis, and will also contribute to future research aimed at the development of effective anti-fibrotic therapeutic strategies targeting the JAK/STAT3 signaling.

Hypertensive Heart Disease: A Narrative Review Series-Part 1: Pathophysiology and Microstructural Changes.

Sustained hypertension causes structural, functional, and neurohumoral abnormalities in the heart, a disease commonly termed hypertensive heart disease (HHD). Modern concepts of HHD, including processes of remodeling leading to the development of various LVH patterns, HF patterns accompanied by micro- and macrovasculopathies, and heart rhythm and conduction disturbances, are missing in the available definitions, despite copious studies being devoted to the roles of myocardial and vascular fibrosis, and neurohumoral and sympathetic regulation, in HHD development and progression. No comprehensive and generally accepted universal definition and classification of HHD is available to date, implementing diagnostic criteria that incorporate all the possible changes and adaptions to the heart. The aim of this review series is to summarize the relevant literature and data, leading to a proposal of a definition and classification of HHD. This first article reviews the processes of initial myocardial remodeling, and myocardial and vascular fibrosis, occurring in HHD. We discuss important pathophysiological and microstructural changes, the different patterns of fibrosis, and the biomarkers and imaging used to detect fibrosis in HHD. Furthermore, we review the possible methods of targeting myocardial fibrosis in HHD, and highlight areas for further research.

Treatment of cardiac fibrosis: from neuro-hormonal inhibitors to CAR-T cell therapy.

Cardiac fibrosis is characterized by the deposition of extracellular matrix proteins in the spaces between cardiomyocytes following both acute and chronic tissue damage events, resulting in the remodeling and stiffening of heart tissue. Fibrosis plays an important role in the pathogenesis of many cardiovascular disorders, including heart failure and myocardial infarction. Several studies have identified fibroblasts, which are induced to differentiate into myofibroblasts in response to various types of damage, as the most important cell types involved in the fibrotic process. Some drugs, such as inhibitors of the renin-angiotensin-aldosterone system, have been shown to be effective in reducing cardiac fibrosis. There are currently no drugs with primarily anti-fibrotic action approved for clinical use, as well as the evidence of a clinical efficacy of these drugs is extremely limited, despite the numerous encouraging results from experimental studies. A new approach is represented by the use of CAR-T cells engineered in vivo using lipid nanoparticles containing mRNA coding for a receptor directed against the FAP protein, expressed by cardiac myofibroblasts. This strategy has proved to be safe and effective in reducing myocardial fibrosis and improving cardiac function in mouse models of cardiac fibrosis. Clinical studies are required to test this novel approach in humans.

Novel Therapies for the Treatment of Cardiac Fibrosis Following Myocardial Infarction.

Cardiac fibrosis is a common pathological consequence of most myocardial diseases. It is associated with the excessive accumulation of extracellular matrix proteins as well as fibroblast differentiation into myofibroblasts in the cardiac interstitium. This structural remodeling often results in myocardial dysfunctions such as arrhythmias and impaired systolic function in patients with heart conditions, ultimately leading to heart failure and death. An understanding of the precise mechanisms of cardiac fibrosis is still limited due to the numerous signaling pathways, cells, and mediators involved in the process. This review article will focus on the pathophysiological processes associated with the development of cardiac fibrosis. In addition, it will summarize the novel strategies for anti-fibrotic therapies such as epigenetic modifications, miRNAs, and CRISPR technologies as well as various medications in cellular and animal models.

Myocardial Fibrosis in Heart Failure: Anti-Fibrotic Therapies and the Role of Cardiovascular Magnetic Resonance in Drug Trials.

All heart muscle diseases that cause chronic heart failure finally converge into one dreaded pathological process that is myocardial fibrosis. Myocardial fibrosis predicts major adverse cardiovascular events and death, yet we are still missing the targeted therapies capable of halting and/or reversing its progression. Fundamentally it is a problem of disproportionate extracellular collagen accumulation that is part of normal myocardial ageing and accentuated in certain disease states. In this article we discuss the role of cardiovascular magnetic resonance (CMR) imaging biomarkers to track fibrosis and collate results from the most promising animal and human trials of anti-fibrotic therapies to date. We underscore the ever-growing role of CMR in determining the efficacy of such drugs and encourage future trialists to turn to CMR when designing their surrogate study endpoints.

Small Molecule KRAS Inhibitors: The Future for Targeted Pancreatic Cancer Therapy?

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest solid tumors in the world. Currently, there are no approved targeted therapies for PDAC. Mutations in Kirsten rat sarcoma viral oncogene homologue (KRAS) are known to be a major driver of PDAC progression, but it was considered an undruggable target until recently. Moreover, PDAC also suffers from drug delivery issues due to the highly fibrotic tumor microenvironment. In this perspective, we provide an overview of recent developments in targeting mutant KRAS and strategies to overcome drug delivery issues (e.g., nanoparticle delivery). Overall, we propose that the antitumor effects from novel KRAS inhibitors along with strategies to overcome drug delivery issues could be a new therapeutic way forward in PDAC.

The Current State of the Art in Acute Kidney Injury.

Decades of pre-clinical research have revealed biologic pathways that have suggested potential therapies for acute kidney injury (AKI) in experimental models. However, translating these to human AKI has largely yielded disappointing results. Fortunately, recent discoveries in AKI molecular mechanisms are providing new opportunities for early detection and novel interventions. This review identifies technologies that are revealing the exceptionally complex nature of the normal kidney, the remarkable heterogeneity of the AKI syndrome, and the myriad responses of the kidney to AKI. Based on the current state of the art, novel approaches to improve the bench-to-bedside translation of novel discoveries are proposed. These strategies include the use of unbiased approaches to improve our understanding of human AKI, establishment of irrefutable biologic plausibility for proposed biomarkers and therapies, identification of patients at risk for AKI pre-injury using clinical scores and non-invasive biomarkers, initiation of safe, and effective preventive interventions of pre-injury in susceptible patients, identification of patients who may develop AKI post-injury using electronic triggers, clinical scores, and novel biomarkers, employment of sequential biomarkers to initiate appropriate therapies based on knowledge of the underlying pathophysiology, use of new biomarkers as criteria for enrollment in randomized clinical trials, assessing efficacy, and empowering the drug development process, and early initiation of anti-fibrotic therapies. These strategies are immediately actionable and hold tremendous promise for effective bench-to-bedside translation of novel discoveries that will change the current dismal prognosis of human AKI.

Understanding the Role of Adenosine Receptors in the Myofibroblast Transformation in Peyronie's Disease.

BACKGROUND: Peyronie's disease (PD) is a chronic fibrotic disease of the penis affecting a significant number of men worldwide without effective medical treatments. Myofibroblasts are pivotal in the pathogenesis of PD. Adenosine and adenosine receptors have been suggested to be involved in the pathophysiology of fibrosis. AIM: To understand the role of adenosine receptors in myofibroblast transformation in PD. METHODS: Fibroblasts were isolated from the non-PD tunica albuginea (TA) tissue and PD plaque tissue and were transformed into myofibroblasts using transforming growth factor (TGF)-ß1. Quantification of α-smooth muscle actin and adenosine receptors (adenosine receptor A1 [ADORA1], adenosine receptor A2A, adenosine receptor A2B [ADORA2B], and adenosine receptor A3) was performed using immuno-cytochemistry, in-cell enzyme-linked immuno-sorbent assay (ICE), and real-time reverse transcription quantitative polymerase chain reaction. The effect of various adenosine receptor agonists or antagonists on TGF-ß1-induced myofibroblast transformation was measured using ICE. OUTCOMES: Expression of adenosine receptors in myofibroblasts obtained from human TA and the effect of adenosine receptor ligands on myofibroblast transformation were investigated. RESULTS: The experiments showed that the protein and messenger RNA levels of α-smooth muscle actin in non-PD TA cells and PD plaque-derived cells were significantly higher in cells exposed to TGF-ß1 than those not treated with TGF-ß1. 2 of 4 adenosine receptors (ADORA1 and ADORA2B) were found to be expressed in both cell populations. Among various adenosine receptor agonists/antagonist investigated, only ADORA2B agonist, BAY 60-6583, significantly inhibited myofibroblast transformation in a concentration-dependent manner when applied simultaneously with TGF-ß1 (IC50 = 30 µmol/L). CLINICAL TRANSLATION: ADORA2B agonists may be clinically efficacious in early-stage PD. STRENGTHS & LIMITATIONS: The strength of this study is the use of primary fibroblasts from human TA. Limitation of the study is the high concentrations of the ligands used. CONCLUSION: The effect of an ADORA2B agonist on TGF-ß1-induced myofibroblast transformation shows a novel potential therapeutic target for PD if applied during early, non-stable phase of PD. Mateus M, Ilg MM, Stebbeds WJ, et al. Understanding the Role of Adenosine Receptors in the Myofibroblast Transformation in Peyronie's Disease. J Sex Med 2018;15:947-957.

BRD4 inhibition for the treatment of pathological organ fibrosis.

Fibrosis is defined as excess deposition of extracellular matrix, resulting in tissue scarring and organ dysfunction. It is estimated that 45% of deaths in the developed world are due to fibrosis-induced organ failure. Despite the well-accepted role of fibrosis in the pathogenesis of numerous diseases, there are only two US Food and Drug Administration-approved anti-fibrotic therapies, both of which are currently restricted to the treatment of pulmonary fibrosis. Thus, organ fibrosis represents a massive unmet medical need. Here, we review recent findings suggesting that an epigenetic regulatory protein, BRD4, is a nodal effector of organ fibrosis, and we highlight the potential of small-molecule BRD4 inhibitors for the treatment of diverse fibrotic diseases.

A Clinical Perspective of Anti-Fibrotic Therapies for Cardiovascular Disease.

Cardiac fibrosis are central to various cardiovascular diseases. Research on the mechanisms and therapeutic targets for cardiac fibrosis has advanced greatly in recent years. However, while many anti-fibrotic treatments have been studied in animal models and seem promising, translation of experimental findings into human patients has been rather limited. Thus, several potential new treatments which have shown to reduce cardiac fibrosis in animal models have either not been tested in humans or proved to be disappointing in clinical trials. A majority of clinical studies are of small size or have not been maintained for long enough periods. In addition, although some conventional therapies, such as renin-angiotensin-aldosterone system (RAAS) inhibitors, have been shown to reduce cardiac fibrosis in humans, cardiac fibrosis persists in patients with heart failure even when treated with these conventional therapies, indicating a need to develop novel and effective anti-fibrotic therapies in cardiovascular disease. In this review article, we summarize anti-fibrotic therapies for cardiovascular disease in humans, discuss the limitations of currently used therapies, along with possible reasons for the failure of so many anti-fibrotic drugs at the clinical level. We will then explore the future directions of anti-fibrotic therapies on cardiovascular disease, and this will include emerging anti-fibrotics that show promise, such as relaxin. A better understanding of the differences between animal models and human pathology, and improved insight into carefully designed trials on appropriate end-points and appropriate dosing need to be considered to identify more effective anti-fibrotics for treating cardiovascular fibrosis in human patients.

Homing in on the hepatic scar: recent advances in cell-specific targeting of liver fibrosis.

Despite the high prevalence of liver disease globally, there are currently no approved anti-fibrotic therapies to treat patients with liver fibrosis. A major goal in anti-fibrotic therapy is the development of drug delivery systems that allow direct targeting of the major pro-scarring cell populations within the liver (hepatic myofibroblasts) whilst not perturbing the homeostatic functions of other mesenchymal cell types present within both the liver and other organ systems. In this review we will outline some of the recent advances in our understanding of myofibroblast biology, discussing both the origin of myofibroblasts and possible myofibroblast fates during hepatic fibrosis progression and resolution. We will then discuss the various strategies currently being employed to increase the precision with which we deliver potential anti-fibrotic therapies to patients with liver fibrosis.