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The heart requires fatty acids to maintain its activity. Various mechanisms regulate myocardial fatty acid metabolism, such as energy production using fatty acids as fuel, for which it is known that coordinated control of fatty acid uptake, β-oxidation, and mitochondrial oxidative phosphorylation steps are important for efficient adenosine triphosphate (ATP) production without unwanted side effects. The fatty acids taken up by cardiomyocytes are not only used as substrates for energy production but also for the synthesis of triglycerides and the replacement reaction of fatty acid chains in cell membrane phospholipids. Alterations in fatty acid metabolism affect the structure and function of the heart. Recently, breakthrough studies have focused on the key transcription factors that regulate fatty acid metabolism in cardiomyocytes and the signaling systems that modify their functions. In this article, we reviewed the latest research on the role of fatty acid metabolism in the pathogenesis of heart failure and provide an outlook on future challenges.

This review focuses on the pathogenic role of sodium glucose cotransporter (SGLT)-2 in the development of renal dysfunction and heart failure in patients with diabetes, by emphasizing the concept of reno-cardiac syndrome (kidney injury worsens cardiac condition) and by substantiating the deleterious effect of sympathetic overdrive in this context. Furthermore, the review proposes a mechanistic hypothesis to explain the benefits of SGLT2 inhibitors, specifically that SGLT-2 inhibitors reduce sympathetic activation at the renal level. To illustrate this point, several examples from both animal experiments and clinical observations are introduced. The bidirectional interaction of the heart and kidney were deeply implicated as an exacerbator of heart failure and renal failure without diabetes. Renal cortical ischemia and abnormal glucose metabolism of tubular epithelial cells are likely to exist as common pathologies in nondiabetic heart failure patients. It is no wonder why SGLT-2 inhibitors are specifically being studied even in the absence of diabetes, both for heart failure and also for renal failure.

Unprecedented advances in secondary prevention have greatly improved the prognosis of cardiovascular diseases (CVDs); however, CVDs remain a leading cause of death globally. These findings suggest the need to reconsider cardiovascular risk and optimal medical therapy. Numerous studies have shown that inflammation, pro-thrombotic factors, and gene mutations are focused not only on cardiovascular residual risk but also as the next therapeutic target for CVDs. Furthermore, recent clinical trials, such as the Canakinumab Anti-inflammatory Thrombosis Outcomes Study trial, showed the possibility of anti-inflammatory therapy for patients with CVDs. Osteopontin (OPN) is a matricellular protein that mediates diverse biological functions and is involved in a number of pathological states in CVDs. OPN has a two-faced phenotype that is dependent on the pathological state. Acute increases in OPN have protective roles, including wound healing, neovascularization, and amelioration of vascular calcification. By contrast, chronic increases in OPN predict poor prognosis of a major adverse cardiovascular event independent of conventional cardiovascular risk factors. Thus, OPN can be a therapeutic target for CVDs but is not clinically available. In this review, we discuss the role of OPN in the development of CVDs and its potential as a therapeutic target.

Although advances in preventive medicine have greatly improved prognosis, cardiovascular disease (CVD) remains the leading cause of death worldwide. This clearly indicates that there remain residual cardiovascular risks that have not been targeted by conventional therapies. The results of multiple animal studies and clinical trials clearly indicate that inflammation is the most important residual risk and a potential target for CVD prevention. The immune cell network is intricately regulated to maintain homeostasis. Ageing associated changes to the immune system occurs in both innate and adaptive immune cells, however T cells are most susceptible to this process. T-cell changes due to thymic degeneration and homeostatic proliferation, metabolic abnormalities, telomere length shortening, and epigenetic changes associated with aging and obesity may not only reduce normal immune function, but also induce inflammatory tendencies, a process referred to as immunosenescence. Since the disruption of biological homeostasis by T cell immunosenescence is closely related to the development and progression of CVD via inflammation, senescent T cells are attracting attention as a new therapeutic target. In this review, we discuss the relationship between CVD and T cell immunosenescence associated with aging and obesity.

Doxorubicin (DOX) is the most widely used anthracycline anticancer agent; however, its cardiotoxicity limits its clinical efficacy. Numerous studies have elucidated the mechanisms underlying DOX-induced cardiotoxicity, wherein apoptosis has been reported as the most common final step leading to cardiomyocyte death. However, in the past two years, the involvement of ferroptosis, a novel programmed cell death, has been proposed. The purpose of this review is to summarize the historical background that led to each form of cell death, focusing on DOX-induced cardiotoxicity and the molecular mechanisms that trigger each form of cell death. Furthermore, based on this understanding, possible therapeutic strategies to prevent DOX cardiotoxicity are outlined. DNA damage, oxidative stress, intracellular signaling, transcription factors, epigenetic regulators, autophagy, and metabolic inflammation are important factors in the molecular mechanisms of DOX-induced cardiomyocyte apoptosis. Conversely, the accumulation of lipid peroxides, iron ion accumulation, and decreased expression of glutathione and glutathione peroxidase 4 are important in ferroptosis. In both cascades, the mitochondria are an important site of DOX cardiotoxicity. The last part of this review focuses on the significance of the disruption of mitochondrial homeostasis in DOX cardiotoxicity.

Obesity has a pronounced effect on the immune response in systemic organs that results in not only insulin resistance but also altered immune responses to infectious diseases and malignant tumors. Obesity-associated microenvironmental changes alter transcriptional expression and metabolism in T cells, leading to alterations in T-cell differentiation, proliferation, function, and survival. Adipokines, cytokines, and lipids derived from obese visceral adipose tissue (VAT) may also contribute to the systemic T-cell phenotype, resulting in obesity-specific pathogenesis. VAT T cells, which have multiple roles in regulating homeostasis and energy utilization and defending against pathogens, are most susceptible to obesity. In particular, many studies have shown that CD4 T cells are deeply involved in the homeostasis of VAT endocrine and metabolic functions and in obesity-related chronic inflammation. In obesity, macrophages and adipocytes in VAT function as antigen-presenting cells and contribute to the obesity-specific CD4 T-cell response by inducing CD4 T-cell proliferation and differentiation into inflammatory effectors via interactions between major histocompatibility complex class II and T-cell receptors. When obesity persists, prolonged stimulation by leptin and circulating free fatty acids, repetitive antigen stimulation, activating stress responses, and hypoxia induce exhaustion of CD4 T cells in VAT. T-cell exhaustion is characterized by restricted effector function, persistent expression of inhibitory receptors, and a transcriptional state distinct from functional effector and memory T cells. Moreover, obesity causes thymic regression, which may result in homeostatic proliferation of obesity-specific T-cell subsets due to changes in T-cell metabolism and gene expression in VAT. In addition to causing T-cell exhaustion, obesity also accelerates cellular senescence of CD4 T cells. Senescent CD4 T cells secrete osteopontin, which causes further VAT inflammation. The obesity-associated transformation of CD4 T cells remains a negative legacy even after weight loss, causing treatment resistance of obesity-related conditions. This review discusses the marked transformation of CD4 T cells in VAT and systemic organs as a consequence of obesity-related microenvironmental changes.

Glucose filtered in the glomerulus is actively reabsorbed by sodium-glucose co-transporter 2 (SGLT2) in proximal tubular epithelial cells (PTEC) and passively returned to the blood via glucose transporter 2 (GLUT2). Healthy PTEC rely primarily on fatty acid beta-oxidation (FAO) for energy. In phase III trials, SGLT2 inhibitors improved outcomes in diabetic kidney disease (DKD). Tubulointerstitial renal fibrosis due to altered metabolic reprogramming of PTEC might be at the root of the pathogenesis of DKD. Here, we investigated the molecular mechanism of SGLT2 inhibitors’ renoprotective effect by examining transcriptional activity of Spp1, which encodes osteopontin, a key mediator of tubulointerstitial renal fibrosis. With primary cultured PTEC from Spp1-enhanced green fluorescent protein knock-in mice, we proved that in high-glucose conditions, increased SGLT2- and GLUT-mediated glucose uptake is causatively involved in aberrant activation of the glycolytic pathway in PTEC, thereby increasing mitochondrial reactive oxygen species (ROS) formation and transcriptional activation of Spp1. FAO activation did not play a direct role in these processes, but elevated expression of a tubular-specific enzyme, myo-inositol oxygenase, was at least partly involved. Notably, canagliflozin blocked overexpression of myo-inositol oxygenase. In conclusion, SGLT2 inhibitors exerted renoprotective effects by inhibiting aberrant glycolytic metabolism and mitochondrial ROS formation in PTEC in high-glucose conditions.

Various methods have been devised to dissolve hydrogen gas in organ preservation solutions, including use of a hydrogen gas cylinder, electrolysis, or a hydrogen-generating agent. However, these methods require considerable time and effort for preparation. We investigated a practical technique for rapidly dissolving hydrogen gas in organ preservation solutions by using a canister containing hydrogen-absorbing alloy. The efficacy of hydrogen-containing organ preservation solution created by this method was tested in a miniature pig model of kidney transplantation from donors with circulatory arrest. The time required for dissolution of hydrogen gas was only 2-3 minutes. When hydrogen gas was infused into a bag containing cold ETK organ preservation solution at a pressure of 0.06 MPa and the bag was subsequently opened to the air, the dissolved hydrogen concentration remained at 1.0 mg/L or more for 4 hours. After warm ischemic injury was induced by circulatory arrest for 30 minutes, donor kidneys were harvested and perfused for 5 minutes with hydrogen-containing cold ETK solution or hydrogen-free cold ETK solution. The perfusion rate was faster from the initial stage with hydrogen-containing cold ETK solution than with hydrogen-free ETK solution. After storage of the kidney in hydrogen-free preservation solution for 1 hour before transplantation, no urine production was observed and blood flow was not detected in the transplanted kidney at sacrifice on postoperative day 6. In contrast, after storage in hydrogen-containing preservation solution for either 1 or 4 hours, urine was detected in the bladder and blood flow was confirmed in the transplanted kidney. This method of dissolving hydrogen gas in organ preservation solution is a practical technique for potentially converting damaged organs to transplantable organs that can be used safely in any clinical setting where organs are removed from donors.

Hydrogen has therapeutic and preventive effects against various diseases. Although animal and clinical studies have reported promising results, hydrogen distribution in organs after administration remains unclear. Herein, the sequential changes in hydrogen concentration in tissues over time were monitored using a highly sensitive glass microsensor and continuous inhalation of 3% hydrogen gas. The hydrogen concentration was measured in the brain, liver, kidney, mesentery fat and thigh muscle of rats. The maximum concentration, time to saturation, and other measurements representing the dynamics of distribution were obtained from the concentration curves, and the results obtained for different organs were compared. The time to saturation was significantly longer (20.2 vs 6.3–9.4 min. P  = 0.004 in all cases) and increased more gradually in muscle than in the other organs. The maximum concentration was the highest in liver and the lowest in the kidney (29.0 ± 2.6 vs 18.0 ± 2.2 μmol/L; P  = 0.03 in all cases). The concentration varied significantly depending on the organ ( P  = 0.03). These results provide the fundamentals for elucidating the mechanisms underlying the in vivo favourable effects of hydrogen gas in mammalian systems.

Recent advances in pharmacotherapy have markedly improved the prognosis of cardiovascular disease (CVD) but have not completely conquered it. Therapies targeting the NOD-like receptor family pyrin domain containing 3 inflammasome and its downstream cytokines have proven effective in the secondary prevention of cardiovascular events, suggesting that inflammation is a target for treating residual risk in CVD. Neutrophil-induced inflammation has long been recognized as important in the pathogenesis of CVD. Circadian rhythm-related and disease-specific microenvironment changes give rise to neutrophil diversity. Neutrophils are primed by various stimuli, such as chemokines, cytokines, and damage-related molecular patterns, and the activated neutrophils contribute to the inflammatory response in CVD through degranulation, phagocytosis, reactive oxygen species generation, and the release of neutrophil extracellular traps (NETs). In particular, NETs promote immunothrombosis through the interaction with vascular endothelial cells and platelets and are implicated in the development of various types of CVD, such as acute coronary syndrome, deep vein thrombosis, and heart failure. NETs are promising candidates for anti-inflammatory therapy in CVD, and their efficacy has already been demonstrated in various animal models of the disease; however, they have yet to be clinically applied in humans. This narrative review discusses the diversity and complexity of neutrophils in the trajectory of CVD, the therapeutic potential of targeting NETs, and the related clinical issues.