It is recognized that obesity contributes to cardiovascular and metabolic disorders through alterations in the levels of adipocyte-derived cytokines (adipokines). Adiponectin is an adipokine that is ...downregulated in obese individuals. It has beneficial actions on the cardiovascular system by directly acting on the heart and blood vessels, and acute administration of adiponectin can minimize the tissue damage resulting from myocardial infarction. More recent research has been aimed at identifying novel adiponectin-like factors involved in metabolic and cardiovascular regulation. Activation of Akt, a protein kinase involved in cell signaling, has been implicated in the control of skeletal muscle hypertrophy. An experimental mouse model demonstrates that substantial increases in muscle fiber hypertrophy, weight and strength occur upon induction of Akt signaling in skeletal muscle. In a mouse model of obesity, the increase in muscle mass caused by myogenic Akt induction results in diminished fat deposition and improvements in whole body metabolism. Based on these findings a protocol to identify novel muscle-secreted proteins (myokines) that confer the phenotypic changes brought on by myogenic Akt induction has been devised. One of these newly discovered factors, referred to as follistatin-like 1, is able to promote revascularization in ischemic limbs and protect the heart from ischemic stress. (Circ J 2009; 73: 13 - 18)
A number of recent epidemiological studies have associated the clonal expansion of hematopoietic cells, a process referred to as clonal hematopoiesis, with increased mortality. Clonal hematopoiesis ...increases the risk of hematological cancer, but this overall risk cannot account for the increase in mortality in the general population. Surprisingly, these mutations have also been associated with higher rates of cardiovascular disease, suggesting a previously unrecognized link between somatic mutations in hematopoietic cells and chronic disease. Here, we review recent epidemiological and experimental studies on clonal hematopoiesis that relate to cardiovascular disease.
Somatic mosaicism, the occurrence of multiple genetically distinct cell clones within the same tissue, is an evitable consequence of human aging. The hematopoietic system is no exception to this, ...where studies have revealed the presence of expanded blood cell clones carrying mutations in preleukemic driver genes and/or genetic alterations in chromosomes. This phenomenon is referred to as clonal hematopoiesis and is remarkably prevalent in elderly individuals. While clonal hematopoiesis represents an early step toward a hematological malignancy, most individuals will never develop blood cancer. Somewhat unexpectedly, epidemiological studies have found that clonal hematopoiesis is associated with an increase in the risk of all-cause mortality and age-related disease, particularly in the cardiovascular system. Studies using murine models of clonal hematopoiesis have begun to shed light on this relationship, suggesting that driver mutations in mature blood cells can causally contribute to aging and disease by augmenting inflammatory processes. Here we provide an up-to-date review of clonal hematopoiesis within the context of somatic mosaicism and aging and describe recent epidemiological studies that have reported associations with age-related disease. We will also discuss the experimental studies that have provided important mechanistic insight into how driver mutations promote age-related disease and how this knowledge could be leveraged to treat individuals with clonal hematopoiesis.
Synthetic cannabinoids (SCs) are a class of new psychoactive substances (NPSs) that exhibit high affinity binding to the cannabinoid CB1 and CB2 receptors and display a pharmacological profile ...similar to the phytocannabinoid (-)-
-Δ
-tetrahydrocannabinol (THC). SCs are marketed under brand names such as K2 and Spice and are popular drugs of abuse among male teenagers and young adults. Since their introduction in the early 2000s, SCs have grown in number and evolved in structural diversity to evade forensic detection and drug scheduling. In addition to their desirable euphoric and antinociceptive effects, SCs can cause severe toxicity including seizures, respiratory depression, cardiac arrhythmias, stroke and psychosis. Binding of SCs to the CB1 receptor, expressed in the central and peripheral nervous systems, stimulates pertussis toxin-sensitive G proteins (G
/G
) resulting in the inhibition of adenylyl cyclase, a decreased opening of N-type Ca
channels and the activation of G protein-gated inward rectifier (GIRK) channels. This combination of signaling effects dampens neuronal activity in both CNS excitatory and inhibitory pathways by decreasing action potential formation and neurotransmitter release. Despite this knowledge, the relationship between the chemical structure of the SCs and their CB1 receptor-mediated molecular actions is not well understood. In addition, the potency and efficacy of newer SC structural groups has not been determined. To address these limitations, various cell-based assay technologies are being utilized to develop structure versus activity relationships (SAR) for the SCs and to explore the effects of these compounds on noncannabinoid receptor targets. This review focuses on describing and evaluating these assays and summarizes our current knowledge of SC molecular pharmacology.
Traditional risk factors are incompletely predictive of cardiovascular disease development, a leading cause of death in the elderly. Recent epidemiological studies have shown that human aging is ...associated with an increased frequency of somatic mutations in the hematopoietic system, which provide a competitive advantage to a mutant cell, thus allowing for its clonal expansion, a phenomenon known as clonal hematopoiesis. Unexpectedly, these mutations have been associated with a higher incidence of cardiovascular disease, suggesting a previously unrecognized connection between somatic mutations in hematopoietic cells and cardiovascular disease. Here, we provide an up-to-date review of clonal hematopoiesis and its association with aging and cardiovascular disease. We also give a detailed report of the experimental studies that have been instrumental in understanding the relationship between clonal hematopoiesis and cardiovascular disease and have shed light on the mechanisms by which hematopoietic somatic mutations contribute to disease pathology.
The medicinal use of
can be traced back thousands of years to ancient China and Egypt. While marijuana has recently shown promise in managing chronic pain and nausea, scientific investigation of ...cannabis has been restricted due its classification as a schedule 1 controlled substance. A major breakthrough in understanding the pharmacology of cannabis came with the isolation and characterization of the phytocannabinoids
-Δ
-tetrahydrocannabinol (Δ
-THC) and cannabidiol (CBD). This was followed by the cloning of the cannabinoid CB1 and CB2 receptors in the 1990s and the subsequent discovery of the endocannabinoid system. In addition to the major phytocannabinoids, Δ
-THC and CBD, cannabis produces over 120 other cannabinoids that are referred to as minor and/or rare cannabinoids. These cannabinoids are produced in smaller amounts in the plant and are derived along with Δ
-THC and CBD from the parent cannabinoid cannabigerolic acid (CBGA). While our current knowledge of minor cannabinoid pharmacology is incomplete, studies demonstrate that they act as agonists and antagonists at multiple targets including CB1 and CB2 receptors, transient receptor potential (TRP) channels, peroxisome proliferator-activated receptors (PPARs), serotonin 5-HT
receptors and others. The resulting activation of multiple cell signaling pathways, combined with their putative synergistic activity, provides a mechanistic basis for their therapeutic actions. Initial clinical reports suggest that these cannabinoids may have potential benefits in the treatment of neuropathic pain, neurodegenerative diseases, epilepsy, cancer and skin disorders. This review focuses on the molecular pharmacology of the minor cannabinoids and highlights some important therapeutic uses of the compounds.
Clonal hematopoiesis has been associated with increased mortality and cardiovascular disease. This condition can arise from somatic mutations in preleukemic driver genes within hematopoietic ...stem/progenitor cells. Approximately 40 candidate driver genes have been identified, but mutations in only 1 of these genes, TET2 (ten-eleven translocation-2), has been shown to casually contribute to cardiovascular disease in murine models.
To develop a facile system to evaluate the disease characteristics of different clonal hematopoiesis driver genes using lentivirus vector and CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/clustered regularly interspaced short palindromic repeat-associated 9) methodology. Using this methodology, evaluate whether Dnmt3a (DNA cytosine-5-methyltransferase 3a)-a commonly occurring clonal hematopoiesis driver gene-causally contributes to cardiovascular disease.
Lentivirus vectors were used to deliver Cas9 and guide RNA to introduce inactivating mutations in Tet2 and Dnmt3a in lineage-negative bone marrow cells. After implantation into lethally irradiated mice, these cells were engrafted and gave rise to labeled blood cell progeny. When challenged with an infusion of Ang II (angiotensin II), mice with inactivating mutations in Tet2 or Dnmt3a displayed greater cardiac hypertrophy, diminished cardiac function, and greater cardiac and renal fibrosis. In comparison with Tet2, inactivation of Dnmt3a did not lead to detectable expansion of the mutant hematopoietic cells during the time course of these experiments. Tet2 inactivation promoted the expression of IL (interleukin) 1β, IL-6, and Ccl5, whereas Dnmt3a inactivation promoted the expression of Cxcl1 (CXC chemokine ligand), Cxcl2, IL-6, and Ccl5 in a lipopolysaccharide-stimulated macrophage cell line.
Experiments using lentivirus vector/CRISPR methodology provided evidence suggesting that inactivating DNMT3A mutations in hematopoietic cells contributes to cardiovascular disease. Comparative analyses showed that inactivation of Tet2 and Dnmt3 was similar in their ability to promote Ang II-induced cardiac dysfunction and renal fibrosis in mice. However, gene-specific actions were indicated by differences in kinetics of hematopoietic stem/progenitor cell expansion and different patterns of inflammatory gene expression.
Abstract Obesity is a risk factor for various cardiovascular diseases including hypertension, atherosclerosis, and myocardial infarction. Recent studies aimed at understanding the microenvironment of ...adipose tissue and its impact on systemic metabolism have shed light on the pathogenesis of obesity-linked cardiovascular diseases. Adipose tissue functions as an endocrine organ by secreting multiple immune-modulatory proteins known as adipokines. Obesity leads to increased expression of pro-inflammatory adipokines and diminished expression of anti-inflammatory adipokines, resulting in the development of a chronic, low-grade inflammatory state. This adipokine imbalance is thought to be a key event in promoting both systemic metabolic dysfunction and cardiovascular disease. This review will focus on the adipose tissue microenvironment and the role of adipokines in modulating systemic inflammatory responses that contribute to cardiovascular disease.
Postnatal growth of the heart is primarily achieved through hypertrophy of individual myocytes. Cardiac growth observed in athletes represents adaptive or physiological hypertrophy, whereas cardiac ...growth observed in patients with hypertension or valvular heart diseases is called maladaptive or pathological hypertrophy. These two types of hypertrophy are morphologically, functionally, and molecularly distinct from each other. The serine/threonine protein kinase Akt is activated by various extracellular stimuli in a phosphatidylinositol-3 kinase-dependent manner and regulates multiple aspects of cellular functions including survival, growth and metabolism. In this review we will discuss the role of the Akt signaling pathway in the heart, focusing on the regulation of cardiac growth, contractile function, and coronary angiogenesis. How this signaling pathway contributes to the development of physiological/pathological hypertrophy and heart failure will also be discussed.
Akt is a serine/threonine protein kinase that is activated by a number of growth factors and cytokines in a phosphatidylinositol-3 kinase-dependent manner. Although antiapoptotic activity of Akt is ...well known, it also regulates other aspects of cellular functions, including migration, glucose metabolism, and protein synthesis. In this review, Akt signaling in endothelial cells and its critical roles in the regulation of vascular homeostasis and angiogenesis will be discussed.
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