-
Advanced Drug Delivery Reviews Jun 2021Cardiac fibrosis remains an unresolved problem in heart diseases. After initial injury, cardiac fibroblasts (CFs) are activated and subsequently differentiate into... (Review)
Review
Cardiac fibrosis remains an unresolved problem in heart diseases. After initial injury, cardiac fibroblasts (CFs) are activated and subsequently differentiate into myofibroblasts (myoFbs) that are major mediator cells in the pathological remodeling. MyoFbs exhibit proliferative and secretive characteristics, and contribute to extracellular matrix (ECM) turnover, collagen deposition. The persistent functions of myoFbs lead to fibrotic scars and cardiac dysfunction. The anti-fibrotic treatment is hindered by the elusive mechanism of fibrosis and lack of specific targets on myoFbs. In this review, we will outline the progress of cardiac fibrosis and its contributions to the heart failure. We will also shed light on the role of myoFbs in the regulation of adverse remodeling. The communication between myoFbs and other cells that are involved in the heart injury and repair respectively will be reviewed in detail. Then, recently developed therapeutic strategies to treat fibrosis will be summarized such as i) chimeric antigen receptor T cell (CAR-T) therapy with an optimal target on myoFbs, ii) direct reprogramming from stem cells to quiescent CFs, iii) "off-target" small molecular drugs. The application of nano/micro technology will be discussed as well, which is involved in the construction of cell-based biomimic platforms and "pleiotropic" drug delivery systems.
Topics: Animals; Drug Delivery Systems; Extracellular Matrix; Fibrosis; Humans; Myocardium; Myofibroblasts; Pharmaceutical Preparations
PubMed: 33831476
DOI: 10.1016/j.addr.2021.03.021 -
Developmental Cell Feb 2016Adult humans fail to regenerate their hearts following injury, and this failure to regenerate myocardium is a leading cause of heart failure and death worldwide.... (Review)
Review
Adult humans fail to regenerate their hearts following injury, and this failure to regenerate myocardium is a leading cause of heart failure and death worldwide. Although all adult mammals appear to lack significant cardiac regeneration potential, some vertebrates can regenerate myocardium throughout life. In addition, new studies indicate that mammals have cardiac regeneration potential during development and very soon after birth. The mechanisms of heart regeneration among model organisms, including neonatal mice, appear remarkably similar. Orchestrated waves of inflammation, matrix deposition and remodeling, and cardiomyocyte proliferation are commonly seen in heart regeneration models. Understanding why adult mammals develop extensive scarring instead of regeneration is a crucial goal for regenerative biology.
Topics: Animals; Cell Proliferation; Heart; Humans; Mammals; Myocardium; Myocytes, Cardiac; Regeneration
PubMed: 26906733
DOI: 10.1016/j.devcel.2016.01.018 -
Nature Reviews. Cardiology Aug 2017Cardiac fibroblasts deposit and maintain extracellular matrix during organogenesis and under physiological conditions. In the adult heart, activated cardiac fibroblasts... (Review)
Review
Cardiac fibroblasts deposit and maintain extracellular matrix during organogenesis and under physiological conditions. In the adult heart, activated cardiac fibroblasts also participate in the healing response after acute myocardial infarction and during chronic disease states characterized by augmented interstitial fibrosis and ventricular remodelling. However, delineation of the characteristics, plasticity, and origins of cardiac fibroblasts is an area of ongoing investigation and controversy. A set of genetic mouse models has been developed that specifically addresses the nature of these cells, in terms of both their origins and their response during cardiac disease and ventricular remodelling. As our understanding of cardiac fibroblasts becomes more defined and refined, so does the potential to develop new therapeutic strategies to control fibrosis and adverse ventricular remodelling.
Topics: Animals; Disease Models, Animal; Extracellular Matrix; Fibroblasts; Fibrosis; Heart; Heart Diseases; Humans; Mice; Myocardium; Ventricular Remodeling
PubMed: 28436487
DOI: 10.1038/nrcardio.2017.57 -
Circulation Research Feb 2018Heart failure and related morbidity and mortality are increasing at an alarming rate, in large part, because of increases in aging, obesity, and diabetes mellitus. The... (Review)
Review
Heart failure and related morbidity and mortality are increasing at an alarming rate, in large part, because of increases in aging, obesity, and diabetes mellitus. The clinical outcomes associated with heart failure are considerably worse for patients with diabetes mellitus than for those without diabetes mellitus. In people with diabetes mellitus, the presence of myocardial dysfunction in the absence of overt clinical coronary artery disease, valvular disease, and other conventional cardiovascular risk factors, such as hypertension and dyslipidemia, has led to the descriptive terminology, diabetic cardiomyopathy. The prevalence of diabetic cardiomyopathy is increasing in parallel with the increase in diabetes mellitus. Diabetic cardiomyopathy is initially characterized by myocardial fibrosis, dysfunctional remodeling, and associated diastolic dysfunction, later by systolic dysfunction, and eventually by clinical heart failure. Impaired cardiac insulin metabolic signaling, mitochondrial dysfunction, increases in oxidative stress, reduced nitric oxide bioavailability, elevations in advanced glycation end products and collagen-based cardiomyocyte and extracellular matrix stiffness, impaired mitochondrial and cardiomyocyte calcium handling, inflammation, renin-angiotensin-aldosterone system activation, cardiac autonomic neuropathy, endoplasmic reticulum stress, microvascular dysfunction, and a myriad of cardiac metabolic abnormalities have all been implicated in the development and progression of diabetic cardiomyopathy. Molecular mechanisms linked to the underlying pathophysiological changes include abnormalities in AMP-activated protein kinase, peroxisome proliferator-activated receptors, O-linked N-acetylglucosamine, protein kinase C, microRNA, and exosome pathways. The aim of this review is to provide a contemporary view of these instigators of diabetic cardiomyopathy, as well as mechanistically based strategies for the prevention and treatment of diabetic cardiomyopathy.
Topics: Animals; Diabetic Cardiomyopathies; Humans; Insulin; Myocardium; Signal Transduction
PubMed: 29449364
DOI: 10.1161/CIRCRESAHA.117.311586 -
Cell Metabolism May 2017Exercise elicits coordinated multi-organ responses including skeletal muscle, vasculature, heart, and lung. In the short term, the output of the heart increases to meet... (Review)
Review
Exercise elicits coordinated multi-organ responses including skeletal muscle, vasculature, heart, and lung. In the short term, the output of the heart increases to meet the demand of strenuous exercise. Long-term exercise instigates remodeling of the heart including growth and adaptive molecular and cellular re-programming. Signaling pathways such as the insulin-like growth factor 1/PI3K/Akt pathway mediate many of these responses. Exercise-induced, or physiologic, cardiac growth contrasts with growth elicited by pathological stimuli such as hypertension. Comparing the molecular and cellular underpinnings of physiologic and pathologic cardiac growth has unveiled phenotype-specific signaling pathways and transcriptional regulatory programs. Studies suggest that exercise pathways likely antagonize pathological pathways, and exercise training is often recommended for patients with chronic stable heart failure or following myocardial infarction. Herein, we summarize the current understanding of the structural and functional cardiac responses to exercise as well as signaling pathways and downstream effector molecules responsible for these adaptations.
Topics: Animals; Cardiovascular Diseases; Cardiovascular Physiological Phenomena; Cardiovascular System; Exercise; Gene Regulatory Networks; Heart; Humans; Metabolic Networks and Pathways; Myocardium
PubMed: 28467921
DOI: 10.1016/j.cmet.2017.04.025 -
Nature Reviews. Cardiology Sep 2018Cardiovascular disease is the leading cause of morbidity and mortality worldwide. Advancing age is a major risk factor for developing cardiovascular disease because of... (Review)
Review
Cardiovascular disease is the leading cause of morbidity and mortality worldwide. Advancing age is a major risk factor for developing cardiovascular disease because of the lifelong exposure to cardiovascular risk factors and specific alterations affecting the heart and the vasculature during ageing. Indeed, the ageing heart is characterized by structural and functional changes that are caused by alterations in fundamental cardiomyocyte functions. In particular, the myocardium is heavily dependent on mitochondrial oxidative metabolism and is especially susceptible to mitochondrial dysfunction. Indeed, primary alterations in mitochondrial function, which are subsequently amplified by defective quality control mechanisms, are considered to be major contributing factors to cardiac senescence. In this Review, we discuss the mechanisms linking defective mitochondrial quality control mechanisms (that is, proteostasis, biogenesis, dynamics, and autophagy) to organelle dysfunction in the context of cardiac ageing. We also illustrate relevant molecular pathways that might be exploited for the prevention and treatment of age-related heart dysfunction.
Topics: Aging; Animals; Cellular Senescence; Heart; Humans; Mice; Mitochondria; Myocardium; Myocytes, Cardiac; Rats
PubMed: 30042431
DOI: 10.1038/s41569-018-0059-z -
Frontiers in Endocrinology 2020Cardiovascular diseases have become the leading cause of human death. Aging is an independent risk factor for cardiovascular diseases. Cardiac aging is associated with... (Review)
Review
Cardiovascular diseases have become the leading cause of human death. Aging is an independent risk factor for cardiovascular diseases. Cardiac aging is associated with maladaptation of cellular metabolism, dysfunction (or senescence) of cardiomyocytes, a decrease in angiogenesis, and an increase in tissue scarring (fibrosis). These events eventually lead to cardiac remodeling and failure. Senescent cardiomyocytes show the hallmarks of DNA damage, endoplasmic reticulum stress, mitochondria dysfunction, contractile dysfunction, hypertrophic growth, and senescence-associated secreting phenotype (SASP). Metabolism within cardiomyocytes is essential not only to fuel the pump function of the heart but also to maintain the functional homeostasis and participate in the senescence of cardiomyocytes. The senescence of cardiomyocyte is also regulated by the non-myocytes (endothelial cells, fibroblasts, and immune cells) in the local microenvironment. On the other hand, the senescent cardiomyocytes alter their phenotypes and subsequently affect the non-myocytes in the local microenvironment and contribute to cardiac aging and pathological remodeling. In this review, we first summarized the hallmarks of the senescence of cardiomyocytes. Then, we discussed the metabolic switch within senescent cardiomyocytes and provided a discussion of the cellular communications between dysfunctional cardiomyocytes and non-myocytes in the local microenvironment. We also addressed the functions of metabolic regulators within non-myocytes in modulating myocardial microenvironment. Finally, we pointed out some interesting and important questions that are needed to be addressed by further studies.
Topics: Animals; Cardiovascular Diseases; Cell Communication; Cellular Senescence; DNA Damage; Endoplasmic Reticulum Stress; Humans; Mitochondria; Myocardium; Myocytes, Cardiac
PubMed: 32508749
DOI: 10.3389/fendo.2020.00280 -
Signal Transduction and Targeted Therapy Mar 2023Cardiac aging is evident by a reduction in function which subsequently contributes to heart failure. The metabolic microenvironment has been identified as a hallmark of... (Review)
Review
Cardiac aging is evident by a reduction in function which subsequently contributes to heart failure. The metabolic microenvironment has been identified as a hallmark of malignancy, but recent studies have shed light on its role in cardiovascular diseases (CVDs). Various metabolic pathways in cardiomyocytes and noncardiomyocytes determine cellular senescence in the aging heart. Metabolic alteration is a common process throughout cardiac degeneration. Importantly, the involvement of cellular senescence in cardiac injuries, including heart failure and myocardial ischemia and infarction, has been reported. However, metabolic complexity among human aging hearts hinders the development of strategies that targets metabolic susceptibility. Advances over the past decade have linked cellular senescence and function with their metabolic reprogramming pathway in cardiac aging, including autophagy, oxidative stress, epigenetic modifications, chronic inflammation, and myocyte systolic phenotype regulation. In addition, metabolic status is involved in crucial aspects of myocardial biology, from fibrosis to hypertrophy and chronic inflammation. However, further elucidation of the metabolism involvement in cardiac degeneration is still needed. Thus, deciphering the mechanisms underlying how metabolic reprogramming impacts cardiac aging is thought to contribute to the novel interventions to protect or even restore cardiac function in aging hearts. Here, we summarize emerging concepts about metabolic landscapes of cardiac aging, with specific focuses on why metabolic profile alters during cardiac degeneration and how we could utilize the current knowledge to improve the management of cardiac aging.
Topics: Humans; Aging; Heart Failure; Molecular Biology; Myocardium; Myocytes, Cardiac; Cellular Senescence; Heart Diseases
PubMed: 36918543
DOI: 10.1038/s41392-023-01378-8 -
International Journal of Molecular... May 2019Cardiac hypertrophy is an adaptive and compensatory mechanism preserving cardiac output during detrimental stimuli. Nevertheless, long-term stimuli incite chronic... (Review)
Review
Cardiac hypertrophy is an adaptive and compensatory mechanism preserving cardiac output during detrimental stimuli. Nevertheless, long-term stimuli incite chronic hypertrophy and may lead to heart failure. In this review, we analyze the recent literature regarding the role of ERK (extracellular signal-regulated kinase) activity in cardiac hypertrophy. ERK signaling produces beneficial effects during the early phase of chronic pressure overload in response to G protein-coupled receptors (GPCRs) and integrin stimulation. These functions comprise (i) adaptive concentric hypertrophy and (ii) cell death prevention. On the other hand, ERK participates in maladaptive hypertrophy during hypertension and chemotherapy-mediated cardiac side effects. Specific ERK-associated scaffold proteins are implicated in either cardioprotective or detrimental hypertrophic functions. Interestingly, ERK phosphorylated at threonine 188 and activated ERK5 (the big MAPK 1) are associated with pathological forms of hypertrophy. Finally, we examine the connection between ERK activation and hypertrophy in (i) transgenic mice overexpressing constitutively activated RTKs (receptor tyrosine kinases), (ii) animal models with mutated sarcomeric proteins characteristic of inherited hypertrophic cardiomyopathies (HCMs), and (iii) mice reproducing syndromic genetic RASopathies. Overall, the scientific literature suggests that during cardiac hypertrophy, ERK could be a "good" player to be stimulated or a "bad" actor to be mitigated, depending on the pathophysiological context.
Topics: Animals; Cardiomegaly; Humans; MAP Kinase Signaling System; Myocardium
PubMed: 31052420
DOI: 10.3390/ijms20092164 -
Lipids in Health and Disease Feb 2020Hyperlipidemia is a common metabolic disorder and one of risk factors for cardiovascular disease. Clinical studies have shown that hyperlipidemia increases the risk of... (Review)
Review
Hyperlipidemia is a common metabolic disorder and one of risk factors for cardiovascular disease. Clinical studies have shown that hyperlipidemia increases the risk of non-ischemic heart failure, while decreasing serum lipids can reverse heart dysfunction. Apart from indirectly affecting the function of the heart by promoting the development of atherosclerosis, hyperlipidemia also affects the systolic function and cardiac electrophysiological response of the heart directly, which may be related to gradual accumulation of cardiac lipids and consequent systemic oxidative stress, proinflammatory state and mitochondrial dysfunction. However, the mechanism underlying direct effects of hyperlipidemia on the heart are not fully understood. In this review, we provide an updated summary of recent experimental and clinical studies that focus on elucidating the mechanisms of the action of hyperlipidemia on cardiac function, the relationship between heart failure and serum lipids, and protective effects of lipid-lowering drugs on the heart. The exciting progress in this field supports the prospect of guiding early protection of the heart to benefit the patients with chronic hyperlipidemia and familial hyperlipidemia.
Topics: Heart Failure; Humans; Hyperlipidemias; Hypolipidemic Agents; Myocardium; Oxidative Stress
PubMed: 32035485
DOI: 10.1186/s12944-019-1171-8