Blockade of MyD88 attenuates cardiac hypertrophy and decreases cardiac myocyte apoptosis in pressure overload-induced cardiac hypertrophy in vivo

In this study, we evaluated whether blocking myeloid differentiation factor-88 (MyD88) could decrease cardiac myocyte apoptosis following pressure overload. Adenovirus expressing dominant negative MyD88 (Ad5-dnMyD88) or Ad5-green fluorescent protein (GFP) (Ad5-GFP) was transfected into rat hearts (n = 8/group) immediately followed by aortic banding for 3 wk. One group of rats (n = 8) was subjected to aortic banding for 3 wk without transfection. Sham surgical operation (n = 8) served as control. The ratios of heart weight to body weight (HW/BW) and heart weight to tibia length (HW/TL) were calculated. Cardiomyocyte size was examined by FITC-labeled wheat germ agglutinin staining of membranes. Cardiac myocyte apoptosis was determined by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay, and myocardial interstitial fibrosis was examined by Masson's Trichrome staining. Aortic banding significantly increased the HW/BW by 41.0% (0.44 +/- 0.013 vs. 0.31 +/- 0.008), HW/TL by 47.2% (42.7 +/- 1.30 vs. 29.0 +/- 0.69), cardiac myocyte size by 49.6%, and cardiac myocyte apoptosis by 11.5%, and myocardial fibrosis and decreased cardiac function compared with sham controls. Transfection of Ad5-dnMyD88 significantly reduced the HW/BW by 18.2% (0.36 +/- 0.006 vs. 0.44 +/- 0.013) and HW/TL by 22.3% (33.2 +/- 0.95 vs. 42.7 +/- 1.30) and decreased cardiomyocyte size by 56.8%, cardiac myocyte apoptosis by 76.2%, as well as fibrosis, and improved cardiac function compared with aortic-banded group. Our results suggest that MyD88 is an important component in the Toll-like receptor-4-mediated nuclear factor-kappaB activation pathway that contributes to the development of cardiac hypertrophy. Blockade of MyD88 significantly reduced cardiac hypertrophy, cardiac myocyte apoptosis, and improved cardiac function in vivo.     

Senescent cardiac fibroblasts: A key role in cardiac fibrosis

Cardiac fibroblasts are a cell population that controls the homeostasis of the extracellular matrix and orchestrates a damage response to maintain cardiac architecture and performance. Due to these functions, fibroblasts play a central role in cardiac fibrosis development, and there are large differences in matrix protein secretion profiles between fibroblasts from aged versus young animals.Senescence is a multifactorial and complex process that has been associated with inflammatory and fibrotic responses. After damage, transient cellular senescence is usually beneficial, as these cells promote tissue repair. However, the persistent presence of senescent cells within a tissue is linked with fibrosis development and organ dysfunction, leading to aging-related diseases such as cardiovascular pathologies. In the heart, early cardiac fibroblast senescence after myocardial infarction seems to be protective to avoid excessive fibrosis; however, in non-infarcted models of cardiac fibrosis, cardiac fibroblast senescence has been shown to be deleterious. Today, two new classes of drugs, termed senolytics and senostatics, which eliminate senescent cells or modify senescence-associated secretory phenotype, respectively, arise as novel therapeutical strategies to treat aging-related pathologies. However, further studies will be needed to evaluate the extent of the utility of senotherapeutic drugs in cardiac diseases, in which pathological context and temporality of the intervention must be considered.     

Vinculin localization in cardiac muscle

Vinculin isolated from chicken cardiac muscle crossreacts with antibodies against smooth muscle vinculin. Antibodies to vinculin were used for localization of vinculin in cardiac muscle by indirect immunofluorescence method. In cardiac muscle vinculin was localized in intercalated discs and near plasma membrane at the cell periphery between external myofibrils and sarcolemma. It was suggested that vinculin plays an important role in myofibril-sarcolemma interaction in cardiac muscle.     

Trends in cardiac pacemaker batteries

Batteries used in Implantable cardiac pacemakers-present unique challenges to their developers and manufacturers in terms of high levels of safety and reliability. In addition, the batteries must have longevity to avoid frequent replacements. Technological advances in leads/electrodes have reduced energy requirements by two orders of magnitude. Micro-electronics advances sharply reduce internal current drain concurrently decreasing size and increasing functionality, reliability, and longevity. It is reported that about 600,000 pacemakers are implanted each year worldwide and the total number of people with various types of implanted pacemaker has already crossed 3 million. A cardiac pacemaker uses half of its battery power for cardiac stimulation and the other half for housekeeping tasks such as monitoring and data logging. The first implanted cardiac pacemaker used nickel-cadmium rechargeable battery, later on zinc-mercury battery was developed and used which lasted for over 2 years. Lithium iodine battery invented and used by Wilson Greatbatch and his team in 1972 made the real impact to implantable cardiac pacemakers. This battery lasts for about 10 years and even today is the power source for many manufacturers of cardiac pacemakers. This paper briefly reviews various developments of battery technologies since the inception of cardiac pacemaker and presents the alternative to lithium iodine battery for the near future.     

The role of cardiac resident macrophage in cardiac aging

Advancements in longevity research have provided insights into the impact of cardiac aging on the structural and functional aspects of the heart. Notable changes include the gradual remodeling of the myocardium, the occurrence of left ventricular hypertrophy, and the decline in both systolic and diastolic functions. Macrophages, a type of immune cell, play a pivotal role in innate immunity by serving as vigilant agents against pathogens, facilitating wound healing, and orchestrating the development of targeted acquired immune responses. Distinct subsets of macrophages are present within the cardiac tissue and demonstrate varied functions in response to myocardial injury. The differentiation of cardiac macrophages according to their developmental origin has proven to be a valuable strategy in identifying reparative macrophage populations, which originate from embryonic cells and reside within the tissue, as well as inflammatory macrophages, which are derived from monocytes and recruited to the heart. These subsets of macrophages possess unique characteristics and perform distinct functions. This review aims to summarize the current understanding of the roles and phenotypes of cardiac macrophages in various conditions, including the steady state, aging, and other pathological conditions. Additionally, it will highlight areas that require further investigation to expand our knowledge in this field.     

The unique functions of cardiac troponin I in the control of cardiac muscle contraction and relaxation

We review development of evidence and current perceptions of the multiple and significant functions of cardiac troponin I in regulation and modulation of cardiac function. Our emphasis is on the unique structure function relations of the cardiac isoform of troponin I, especially regions containing sites of phosphorylation. The data indicate that modifications of specific regions cardiac troponin I by phosphorylations either promote or reduce cardiac contractility. Thus, a homeostatic balance in these phosphorylations is an important aspect of control of cardiac function. A new concept is the idea that the homeostatic mechanisms may involve modifications of intra-molecular interactions in cardiac troponin I.     

Molecular biomarkers in cardiac hypertrophy

Cardiac hypertrophy is characterized by an increase in myocyte size in the absence of cell division. This condition is thought to be an adaptive response to cardiac wall stress resulting from the enhanced cardiac afterload. The pathogenesis of heart dysfunction, which is one of the primary causes of morbidity and mortality in elderly people, is often associated with myocardial remodelling caused by cardiac hypertrophy. In order to well understand the potential mechanisms, we described the molecules involved in the development and progression of myocardial hypertrophy. Increasing evidence has indicated that micro‐RNAs are involved in the pathogenesis of cardiac hypertrophy. In addition, molecular biomarkers including vascular endothelial growth factor B, NAD‐dependent deacetylase sirtuin‐3, growth/differentiation factor 15 and glycoprotein 130, also play important roles in the development of myocardial hypertrophy. Knowing the regulatory mechanisms of these biomarkers in the heart may help identify new molecular targets for the treatment of cardiac hypertrophy.     

Changes in the fluctuation of the contraction rhythm of spontaneously beating cardiac myocytes in cultures with and without cardiac fibroblasts

The heart functions as a syncytium of cardiac myocytes and surrounding supportive non-myocytes such as fibroblasts. There is a possibility that a variety of non-myocyte-derived factors affect the maturation of cardiac myocytes in the development of the heart. Cultured neonatal cardiac myocytes contract spontaneously and cyclically. The fluctuation of beating rhythm varies depending on the strength of coupling through gap junctions among cardiac myocytes, indicating that the development of intercellular communication via gap junctions is crucial to the stability of contraction rhythm in cardiac myocytes. In this study, we aimed at elucidating whether and how cardiac fibroblasts affect the development of cardiac myocytes from the point of view of the changes in the fluctuation of the contraction rhythm of cardiac myocytes in cardiac myocyte–fibroblast co-cultures. The present study suggested that cardiac fibroblasts co-cultured with cardiac myocytes enhanced the intercellular communication among myocytes via gap junctions, thereby stabilizing the spontaneous contraction rhythm of cultured cardiac myocytes.     

Hyperthyroidism facilitates cardiac fatty acid oxidation through altered regulation of cardiac carnitine palmitoyltransferase: studies in vivo and with cardiac myocytes.

The aim was to establish whether increased cardiac fatty acid oxidation in hyperthyroidism is due to direct alterations in cardiac metabolism which favour fatty acid oxidation and/or whether normal regulatory links between changes in glucose supply and fatty acid oxidation are dysfunctional. Euthyroid rats were sampled in the absorptive state or after 48 h starvation. Rats were rendered hyperthyroid by injection of tri-iodothyronine (1000 microg/kg body wt. per day; 3 days). We evaluated the regulatory significance of direct effects of hyperthyroidism by measuring rates of palmitate oxidation in the absence or presence of glucose using cardiac myocytes. The results were examined in relation to the activity/regulatory characteristics of cardiac carnitine palmitoyltransferase (CPT) estimated by measuring rates of [3H]palmitoylcarnitine formation from [3H]carnitine and palmitoyl-CoA by isolated mitochondria. To define the involvement of other hormones, we examined whether hyperthyroidism altered basal or agonist-stimulated cardiac cAMP concentrations in cardiac myocytes and whether the effects of hyperthyroidism could be reversed by 24 h exposure to insulin infused subcutaneously (2 i. u. per day; Alzet osmotic pumps). Rates of 14C-palmitate oxidation (to 14CO2) by cardiac myocytes were significantly increased (1.6 fold; P< 0.05) by hyperthyroidism, whereas the percentage suppression of palmitate oxidation by glucose was greatly diminished. Cardiac CPT activities in mitochondria from hyperthyroid rats were 2-fold higher and the susceptibility of cardiac CPT activity to inhibition by malonyl-CoA was decreased. These effects were not mimicked by 48 h starvation. The decreased susceptibility of cardiac CPT activities to malonyl-CoA inhibition in hyperthyroid rats was normalised by 24 h exposure to elevated insulin concentration. Acute insulin addition did not influence the response to glucose in cardiac myocytes from euthyroid or hyperthyroid rats and basal and agonist-stimulated cAMP concentrations were unaffected by hyperthyroidism in vivo. The data provide insight into possible mechanisms by which hyperthyroidism facilitates fatty acid oxidation by the myocardium, identifying changes in cardiac CPT activity and malonyl-CoA sensitivity that would be predicted to render cardiac fatty acid oxidation less sensitive to external factors influencing malonyl-CoA content, and thereby to favour fatty acid oxidation. The increased CPT activity observed in response to hyperthyroidism may be a consequence of an impaired action of insulin but occurs through a cAMP-independent mechanism.     

Changes in cardiac troponins with gestational age explain changes in cardiac muscle contractility in the sheep fetus

The development of the adult cardiac troponin complex in conjunction with changes in cardiac function and cardiomyocyte binucleation has not been systematically characterized during fetal life in a species where maturation of the cardiomyocytes occurs prenatally as it does in the human. The aim of this study was to correlate the expression of each of the major adult troponin isoforms (T, I, and C) during late gestation (term of 150 days) to changes in both Ca(2+) sensitivity and maximum Ca(2+)-activated force of the contractile apparatus and the maturation of cardiomyocytes. The percentage of mononucleated cardiomyocytes in the right ventricle decreased with gestational age to 46% by 137-142 days of gestation. The length of binucleated cardiomyocytes did not change with gestational age, but the length of binucleated cardiomyocytes relative to heart weight decreased with gestational age. There was no change in the expression of adult cardiac troponin T with increasing gestation. The contractile apparatus was significantly more sensitive to Ca(2+) at 90 days compared with either 132 or 139 days of gestation, consistent with an ～30% increase in the expression of adult cardiac troponin I between 90 and 110 days of gestation. Maximum Ca(2+)-activated force significantly increased from 90 days compared with 130 days consistent with an increase of ～40% in cardiac troponin C protein expression. These data show that increased adult cardiac troponin I and C protein expression across late gestation is consistent with reduced Ca(2+) sensitivity and increased maximum Ca(2+)-activated force. Furthermore, changes in cardiac troponin C, not I, protein expression track with the timing of cardiomyocyte binucleation.     

The protective effect of curcumin on cardiac markers and fibrosis in abemaciclib-induced cardiac damage in rats

Abemaciclib (ABE) is a cyclin-dependent kinase inhibitor used in combination with an antiestrogen in the treatment of breast cancer. In addition to the important therapeutic properties of this drug, its side effects are not fully known. In this study, we aimed to investigate the protective effect of curcumin (CUR) on cardiac damage caused by ABE administration. Forty rats were equally divided into control, dimethyl sulfoxide (150 µL), CUR (30 mg/kg/day), ABE (26 mg/kg/day), and ABE + CUR (26 mg/kg/day ABE and 30mg/kg/day CUR) groups (n = 8). Injections were administered daily for 28 days. Troponin-I, total cholesterol, and creatine kinase myocardial band (CK-MB) levels and cardiac fibrosis were higher in the ABE group than in the control group (p < 0.05), and were lower in the ABE + CUR group than in the ABE group (p < 0.05). The results showed that ABE administration can cause cardiac damage and increase cardiac fibrosis. However, they showed that coadministration of CUR with ABE could suppress increases in CK-MB, troponin-I, and total cholesterol levels and also cardiac fibrosis associated with cardiac damage. Therefore, we can infer that the subsequent administration of CUR ABE treatment can be used as a therapeutic strategy for preventing cardiac damage.     

Altered function and regulation of cardiac ryanodine receptors in cardiac disease

In cardiac muscle, the ryanodine receptor (RyR2) on the sarcoplasmic reticulum (SR) releases the calcium required for muscle contraction. The magnitude of Ca²⁺ release by RyR2, which is subject to regulation by several physiological mediators, determines cardiac contractility. In heart failure, chronic stimulation of the β-adrenergic signaling pathway leads to hyperphosphorylation of RyR2 by protein kinase A, which dissociates calstabin2 (FKBP12.6) from the receptor. Calstabin2-depleted channels display altered channel gating and can cause diastolic Ca²⁺ release from the SR. This release depletes the SR Ca²⁺ stores, leading to reduced myocardial contractility. Mutant RyR2, found in patients with catecholaminergic polymorphic ventricular tachycardia, has decreased calstabin2 binding affinity, which can trigger ventricular arrhythmias and sudden cardiac death after stress and exercise. Thus, defects in RyR2 have been linked to heart failure and exercise-induced sudden cardiac death and might provide novel therapeutic targets for the treatment of these common diseases of the heart.     

Neuregulin-1alpha and beta isoform expression in cardiac microvascular endothelial cells and function in cardiac myocytes in vitro

Neuregulins (NRGs) are a family of alternatively spliced growth factors that act through receptor tyrosine kinases of the epidermal growth factor (EGF) receptor family in diverse tissues. The NRG-erbB signaling axis is a critical mediator of cardiac development, and growing evidence supports a role for this system in the intricate cross-talk between the microvascular endothelium and myocytes in the adult heart. The purpose of this study was first to examine the expression of splice variants of the NRG1 gene in adult rat cardiac microvascular endothelial cells and second to compare the function of these variants in cardiac myocytes. We demonstrate that cardiac microvascular endothelial cells in rat culture express multiple Type I NRG1 gene products, including both alpha and beta variants. Comparison of the activity of recombinant NRG1alpha and NRG1beta EGF-like domain proteins in cardiac myocytes shows that the beta ligand is a more potent activator of receptor phosphorylation and intracellular signaling than the alpha ligand, and only the beta ligand stimulated glucose uptake and protein synthesis in these culture conditions. Thus, cardiac microvascular endothelial cells express multiple NRG1 isotypes, but only beta-variants are biologically active on cardiac myocytes.     

Modelflow underestimates cardiac output in heat-stressed individuals

An estimation of cardiac output can be obtained from arterial pressure waveforms using the Modelflow method. However, whether the assumptions associated with Modelflow calculations are accurate during whole body heating is unknown. This project tested the hypothesis that cardiac output obtained via Modelflow accurately tracks thermodilution-derived cardiac outputs during whole body heat stress. Acute changes of cardiac output were accomplished via lower-body negative pressure (LBNP) during normothermic and heat-stressed conditions. In nine healthy normotensive subjects, arterial pressure was measured via brachial artery cannulation and the volume-clamp method of the Finometer. Cardiac output was estimated from both pressure waveforms using the Modeflow method. In normothermic conditions, cardiac outputs estimated via Modelflow (arterial cannulation: 6.1 ± 1.0 l/min; Finometer 6.3 ± 1.3 l/min) were similar with cardiac outputs measured by thermodilution (6.4 ± 0.8 l/min). The subsequent reduction in cardiac output during LBNP was also similar among these methods. Whole body heat stress elevated internal temperature from 36.6 ± 0.3 to 37.8 ± 0.4°C and increased cardiac output from 6.4 ± 0.8 to 10.9 ± 2.0 l/min when evaluated with thermodilution (P < 0.001). However, the increase in cardiac output estimated from the Modelflow method for both arterial cannulation (2.3 ± 1.1 l/min) and Finometer (1.5 ± 1.2 l/min) was attenuated compared with thermodilution (4.5 ± 1.4 l/min, both P < 0.01). Finally, the reduction in cardiac output during LBNP while heat stressed was significantly attenuated for both Modelflow methods (cannulation: -1.8 ± 1.2 l/min, Finometer: -1.5 ± 0.9 l/min) compared with thermodilution (-3.8 ± 1.19 l/min). These results demonstrate that the Modelflow method, regardless of Finometer or direct arterial waveforms, underestimates cardiac output during heat stress and during subsequent reductions in cardiac output via LBNP.     

Telocytes in exercise‐induced cardiac growth

Exercise can induce physiological cardiac growth, which is featured by enlarged cardiomyocyte cell size and formation of new cardiomyocytes. Telocytes (TCs) are a recently identified distinct interstitial cell type, existing in many tissues and organs including heart. TCs have been shown to form a tandem with cardiac stem/progenitor cells in cardiac stem cell niches, participating in cardiac regeneration and repair. Although exercise‐induced cardiac growth has been confirmed as an important way to promote cardiac regeneration and repair, the response of cardiac TCs to exercise is still unclear. In this study, 4 weeks of swimming training was used to induce robust healthy cardiac growth. Exercise can induce an increase in cardiomyocyte cell size and formation of new cardiomyocytes as determined by Wheat Germ Lectin and EdU staining respectively. TCs were identified by three immunofluorescence stainings including double labelling for CD34/vimentin, CD34/platelet‐derived growth factor (PDGF) receptor‐α and CD34/PDGF receptor‐β. We found that cardiac TCs were significantly increased in exercised heart, suggesting that TCs might help control the activity of cardiac stem/progenitor cells, cardiomyocytes or endothelial cells. Adding cardiac TCs might help promote cardiac regeneration and renewal.     

心肌细胞肥大的信号转导通路

心肌肥厚是肥大刺激诱导核内基因异常表达的结果,细胞内信号转导通路是肥大刺激与核内基因转录活化的偶联环节。然而,淡同刺激诱导的心肌肥大可能具有不同的“分子表型”,这主要取决于它们启动的信号转导通路。对心肌肥大信号转导通路的深入认识,不仅胡助于阐明心肌肥厚的细胞分子机制,而且可为药物干预防治心肌肥厚提供新思路。     

AMPK and cardiac remodelling

Cardiac remodelling is generally accepted as a critical process in the progression of heart failure. Myocyte hypertrophy,inflammatory responses and cardiac fibrosis are the main pathological changes associated with cardiac remodelling.AMP-activated protein kinase(AMPK) is known as an energy sensor and a regulator of cardiac metabolism under normal and ischaemic conditions. Additionally, AMPK has been shown to play roles in cardiac remodelling extending well beyond metabolic regulation. In this review, we discuss the currently defined roles of AMPK in cardiac remodelling and summarize the effects of AMPK on cardiac hypertrophy, inflammatory responses and fibrosis and the molecular mechanisms underlying these effects. In addition, we discuss some pharmacological activators of AMPK that are promising treatments for cardiac remodelling.