The prevalence of diabetes is rapidly increasing and closely associated with cardiovascular morbidity and mortality. While the major cardiovascular complication associated with diabetes is coronary ...artery disease, it is becoming increasingly apparent that diabetes impacts the electrical conduction system in the heart, resulting in atrial fibrillation, and ventricular arrhythmias. The relationship between diabetes and arrhythmias is complex and multifactorial including autonomic dysfunction, atrial and ventricular remodeling and molecular alterations. This review will provide a comprehensive overview of the link between diabetes and arrhythmias with insight into the common molecular mechanisms, structural alterations and therapeutic outcomes.
Cardiovascular disease is a leading cause of death worldwide. Loss of cardiomyocytes that occurs during many types of damage to the heart such as ischemic injury and stress caused by pressure ...overload, diminishes cardiac function due to their limited regenerative capacity and promotes remodeling, which further damages the heart. Cardiomyocyte death occurs through two primary mechanisms, necrosis and apoptosis. Apoptosis is a highly regulated form of cell death that can occur through intrinsic (mitochondrial) or extrinsic (receptor mediated) pathways. Extrinsic apoptosis occurs through a subset of Tumor Necrosis Receptor (TNF) family receptors termed "Death Receptors." While some ligands for death receptors have been extensively studied in the heart, such as TNF-α, others have been virtually unstudied. One poorly characterized cardiac TNF related ligand is TNF-Related Apoptosis Inducing Ligand (TRAIL). TRAIL binds to two apoptosis-inducing receptors, Death Receptor (DR) 4 and DR5. There are also three decoy TRAIL receptors, Decoy Receptor (DcR) 1, DcR2 and osteoprotegerin (OPG). While TRAIL has been extensively studied in the cancer field due to its ability to selectively induce apoptosis in transformed cell types, emerging clinical evidence points towards a role for TRAIL and its receptors in cardiac pathology. This article will highlight our current understanding of TRAIL and its receptors in normal and pathological conditions in the heart.
Heart failure is a leading cause of death worldwide. While there are multiple etiologies contributing to the development of heart failure, all cause result in impairments in cardiac function that is ...characterized by changes in cardiac remodeling and compliance. Fibrosis is associated with nearly all forms of heart failure and is an important contributor to disease pathogenesis. Inflammation also plays a critical role in the heart and there is a large degree of interconnectedness between the inflammatory and fibrotic response. This review discusses the cellular and molecular mechanisms contributing to inflammation and fibrosis and the interplay between the two.
β-Adrenergic receptors (βARs) regulate normal and pathophysiological heart function through their impact on contractility. βARs are also regulators of immune function where they play a unique role ...depending on the disease condition and immune cell type. Emerging evidence suggests an important role for the β2AR subtype in regulating remodeling in the pathological heart; however, the importance of these responses has never been examined. In heart failure, catecholamines are elevated, leading to chronic βAR activation and contributing to the detrimental effects in the heart. We hypothesized that immune cell β2AR plays a critical role in the development of heart failure in response to chronic catecholamine elevations through their regulation of immune cell infiltration. To test this, chimeric mice were generated by performing bone marrow transplant (BMT) experiments using wild-type (WT) or β2AR knockout (KO) donors. WT and β2ARKO BMT mice were chronically administered the βAR agonist isoproterenol. Immune cell recruitment to the heart was examined by histology and flow cytometry. Numerous changes in immune cell recruitment were observed with isoproterenol administration in WT BMT mice including proinflammatory myeloid populations and lymphocytes with macrophages made up the majority of immune cells in the heart and which were absent in β2ARKO BMT animal. β2ARKO BMT mice had decreased cardiomyocyte death, hypertrophy, and interstitial fibrosis following isoproterenol treatment, culminating in improved function. These findings demonstrate an important role for immune cell β2AR expression in the heart's response to chronically elevated catecholamines. NEW & NOTEWORTHY Immune cell β2-adrenergic receptors (β2ARs) are important for proinflammatory macrophage infiltration to the heart in a chronic isoproterenol administration model of heart failure. Mice lacking immune cell β2AR have decreased immune cell infiltration to their heart, primarily proinflammatory macrophage populations. This decrease culminated to decreased cardiac injury with lessened cardiomyocyte death, decreased interstitial fibrosis and hypertrophy, and improved function demonstrating that β2AR regulation of immune responses plays an important role in the heart's response to persistent βAR stimulation.
Abstract
Aims
Myocardial infarction (MI) is the most common cause of heart failure (HF) worldwide. G protein-coupled receptor kinase 5 (GRK5) is upregulated in failing human myocardium and promotes ...maladaptive cardiac hypertrophy in animal models. However, the role of GRK5 in ischemic heart disease is still unknown. In this study, we evaluated whether myocardial GRK5 plays a critical role post-MI in mice and included the examination of specific cardiac immune and inflammatory responses.
Methods and results
Cardiomyocyte-specific GRK5 overexpressing transgenic mice (TgGRK5) and non-transgenic littermate control (NLC) mice as well as cardiomyocyte-specific GRK5 knockout mice (GRK5cKO) and wild type (WT) were subjected to MI and, functional as well as structural changes together with outcomes were studied. TgGRK5 post-MI mice showed decreased cardiac function, augmented left ventricular dimension and decreased survival rate compared to NLC post-MI mice. Cardiac hypertrophy and fibrosis as well as fetal gene expression were increased post-MI in TgGRK5 compared to NLC mice. In TgGRK5 mice, GRK5 elevation produced immuno-regulators that contributed to the elevated and long-lasting leukocyte recruitment into the injured heart and ultimately to chronic cardiac inflammation. We found an increased presence of pro-inflammatory neutrophils and macrophages as well as neutrophils, macrophages and T-lymphocytes at 4-days and 8-weeks respectively post-MI in TgGRK5 hearts. Conversely, GRK5cKO mice were protected from ischemic injury and showed reduced early immune cell recruitment (predominantly monocytes) to the heart, improved contractility and reduced mortality compared to WT post-MI mice. Interestingly, cardiomyocyte-specific GRK2 transgenic mice did not share the same phenotype of TgGRK5 mice and did not have increased cardiac leukocyte migration and cytokine or chemokine production post-MI.
Conclusions
Our study shows that myocyte GRK5 has a crucial and GRK-selective role on the regulation of leucocyte infiltration into the heart, cardiac function and survival in a murine model of post-ischemic HF, supporting GRK5 inhibition as a therapeutic target for HF.
Graphical Abstract
Fibroblasts are an important resident cell population in the heart involved in maintaining homeostasis and structure during normal conditions. They are also crucial in disease states for sensing ...signals and initiating the appropriate repair responses to maintain the structural integrity of the heart. This sentinel role of cardiac fibroblasts occurs, in part, through their ability to secrete cytokines. β-adrenergic receptors (βAR) are also critical regulators of cardiac function in the normal and diseased state and a major therapeutic target clinically. βAR are known to influence cytokine secretion in various cell types and they have been shown to be involved in cytokine production in the heart, but their role in regulating cytokine production in cardiac fibroblasts is not well understood. Thus, we hypothesized that βAR activation on cardiac fibroblasts modulates cytokine production to influence fibroblast function. Using primary fibroblast cultures from neonatal rats and adult mice, increased interleukin (IL)-6 expression and secretion occurred following β2AR activation. The use of pharmacological inhibitors and genetic manipulations showed that IL-6 elevations occurred through the Gαs-mediated activation of ERK1/2 and resulted in increased fibroblast proliferation. In vivo, a lack of β2AR resulted in increased infarct size following myocardial infarction and impaired wound closure in a murine dermal wound healing assay. These findings identify an important role for β2AR in regulating fibroblast proliferation through Gαs/ERK1/2-dependent alterations in IL-6 and may lead to the development of improved heart failure therapies through targeting fibrotic function of β2AR.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Cardiomyocyte survival and death contributes to many cardiac diseases. A common mechanism of cardiomyocyte death is through apoptosis however, numerous death receptors (DR) have been virtually ...unstudied in the context of cardiovascular disease. Previous studies have identified TNF-related apoptosis inducing ligand (TRAIL) and its receptor, DR5, as being altered in a chronic catecholamine administration model of heart failure, and suggest a role of non-canonical signaling in cardiomyocytes. Furthermore, multiple clinical studies have identified TRAIL or DR5 as biomarkers in the prediction of severity and mortality following myocardial infarction and in heart failure development risk suggesting a role of DR5 signaling in the heart. While TRAIL/DR5 have been extensively studied as a potential cancer therapeutic due to their ability to selectively activate apoptosis in cancer cells, TRAIL and DR5 are highly expressed in the heart where their function is uncharacterized. However, many non-transformed cell types are resistant to TRAIL-induced apoptosis suggesting non-canonical functions in non-cancerous cell types. Our goal was to determine the role of DR5 in the heart with the hypothesis that DR5 does not induce cardiomyocyte apoptosis but initiates non-canonical signaling to promote cardiomyocyte growth and survival. Histological analysis of hearts from mice treated with a DR5 agonists showed increased hypertrophy with no differences in cardiomyocyte death, fibrosis or function. Mechanistic studies in the heart and isolated cardiomyocytes identified ERK1/2 activation with DR5 agonist treatment which contributed to hypertrophy. Furthermore, epidermal growth factor receptor (EGFR) was activated following DR5 agonist treatment through activation of MMP and HB-EGFR cleavage and specific inhibitors of MMP and EGFR prevented DR5-mediated ERK1/2 signaling and hypertrophy. Taken together, these studies identify a previously unidentified role for DR5 in the heart, which does not promote apoptosis but acts through non-canonical MMP-EGFR-ERK1/2 signaling mechanisms to contribute to cardiomyocyte hypertrophy.
•Death Receptor (DR) 5 is expressed in cardiomyocytes and activation does not result in classical death receptor signaling•DR5 activation in isolated cardiomyocytes and heart leads to ERK1/2 activation and results in hypertrophy•ERK1/2 activation by DR5 occurs through EGFR-transactivation and GATA4 leading to pro-hypertrophic gene transcription.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
ABSTRACTG protein-coupled receptors (GPCR) remain primary therapeutic targets for numerous cardiovascular disorders, including heart failure (HF), due to their influence on cardiac remodeling in ...response to elevated neurohormone signaling. GPCR blockers have proven to be beneficial in the treatment of HF by reducing chronic G protein activation and cardiac remodeling, thereby extending the lifespan of HF patients. Unfortunately this effect does not persist indefinitely, thus next generation therapeutics aim to selectively block harmful GPCR-mediated pathways while simultaneously promoting beneficial signaling. Transactivation of epidermal growth factor receptor (EGFR) has been shown to be mediated by an expanding repertoire of GPCRs in the heart, and promotes cardiomyocyte survival, thus may offer a new avenue of HF therapeutics. However, GPCR-dependent EGFR transactivation has also been shown to regulate cardiac hypertrophy and fibrosis by different GPCRs, and via distinct molecular mechanisms. Here, we discuss the mechanisms and impact of GPCR-mediated EGFR transactivation in the heart, focusing on angiotensin II, urotensin II and β-adrenergic receptor systems, and highlight areas of research that will help us to determine whether this pathway can be engaged as future therapeutic strategy.
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