Ginsenoside RG1-induced mesenchymal stem cells alleviate diabetic cardiomyopathy through secreting exosomal circNOTCH1 to promote macrophage M2 polarization.

Diabetic cardiomyopathy (DCM) is a cardiac complication resulting from long-term uncontrolled diabetes, characterized by myocardial fibrosis and abnormal cardiac function. This study aimed at investigating the potential of ginsenoside RG1 (RG1)-induced mesenchymal stem cells (MSCs) in alleviating DCM. A DCM mouse model was constructed, and the effects of RG1-induced MSCs on myocardial function and fibrosis in diabetic mice were evaluated. RG1-induced MSCs were cocultured with high glucose-treated fibroblasts for subsequent functional and mechanism assays. It was discovered that RG1-induced MSCs secrete exosomes that induce macrophage M2 polarization. Mechanistically, exosomes derived from RG1-induced MSCs transferred circNOTCH1 into macrophages, activating the NOTCH signaling pathway. A competing endogenous RNA (ceRNA) regulatory axis consisting of circNOTCH1, miR-495-3p, and NOTCH1 was found to contribute to DCM alleviation.. This study unveiled that exosomal circNOTCH1 secreted by RG1-induced MSCs can alleviate DCM by activating the NOTCH signaling pathway to induce macrophage M2 polarization. This finding may contribute to the development of new therapeutic approaches for DCM.

Ferroptosis is essential for diabetic cardiomyopathy and is prevented by sulforaphane via AMPK/NRF2 pathways.

Herein, we define the role of ferroptosis in the pathogenesis of diabetic cardiomyopathy (DCM) by examining the expression of key regulators of ferroptosis in mice with DCM and a new ex vivo DCM model. Advanced glycation end-products (AGEs), an important pathogenic factor of DCM, were found to induce ferroptosis in engineered cardiac tissues (ECTs), as reflected through increased levels of Ptgs2 and lipid peroxides and decreased ferritin and SLC7A11 levels. Typical morphological changes of ferroptosis in cardiomyocytes were observed using transmission electron microscopy. Inhibition of ferroptosis with ferrostatin-1 and deferoxamine prevented AGE-induced ECT remodeling and dysfunction. Ferroptosis was also evidenced in the heart of type 2 diabetic mice with DCM. Inhibition of ferroptosis by liproxstatin-1 prevented the development of diastolic dysfunction at 3 months after the onset of diabetes. Nuclear factor erythroid 2-related factor 2 (NRF2) activated by sulforaphane inhibited cardiac cell ferroptosis in both AGE-treated ECTs and hearts of DCM mice by upregulating ferritin and SLC7A11 levels. The protective effect of sulforaphane on ferroptosis was AMP-activated protein kinase (AMPK)-dependent. These findings suggest that ferroptosis plays an essential role in the pathogenesis of DCM; sulforaphane prevents ferroptosis and associated pathogenesis via AMPK-mediated NRF2 activation. This suggests a feasible therapeutic approach with sulforaphane to clinically prevent ferroptosis and DCM.

CARD9 Regulation and its Role in Cardiovascular Diseases.

Caspase recruitment domain-containing protein 9 (CARD9) is an adaptor protein expressed on myeloid cells and located downstream of pattern recognition receptors (PRRs), which transduces signals involved in innate immunity. CARD9 deficiency is associated with increased susceptibility to various fungal diseases. Increasing evidence shows that CARD9 mediates the activation of p38 MAPK, NF-κB, and NLRP3 inflammasome in various CVDs and then promotes the production of proinflammatory cytokines and chemokines, which contribute to cardiac remodeling and cardiac dysfunction in certain cardiovascular diseases (CVDs). Moreover, CARD9-mediated anti-apoptosis and autophagy are implicated in the progression of CVDs. Here, we summarize the structure and function of CARD9 in innate immunity and its various roles in inflammation, apoptosis, and autophagy in the pathogenesis of CVDs. Furthermore, we discuss the potential therapies targeting CARD9 to prevent CVDs and raise some issues for further exploring the role of CARD9 in CVDs.

Sex differences in the effects of whole-life, low-dose cadmium exposure on postweaning high-fat diet-induced cardiac pathogeneses.

We previously showed the development of cardiac remodeling (hypertrophy or fibrosis) in mice with either post-weaning high-fat diet (HFD, 60% kcal fat) feeding or exposure to chronic low-dose cadmium. Here, we determined whether whole-life exposure to environmentally relevant, low-dose cadmium affects the susceptibility of offspring to post-weaning HFD-induced cardiac pathologies and function. Besides, we also determined whether these effects are sex-dependent. Male and female mice were exposed to cadmium-containing (0, 0.5, or 5 parts per million [ppm]) drinking water before breeding; the pregnant mice and dams with offspring continually drank the same cadmium-containing water. After weaning, the offspring were continued on the same regime as their parents and fed either a HFD or normal fat diet for 24 weeks. Cardiac function was examined with echocardiography. Cardiac tissues were used for the histopathological and biochemical (gene and protein expression by real-time PCR and Western blotting) assays. Results showed a dose-dependent cadmium accumulation in the hearts of male and female mice along with decreased cardiac zinc and copper levels only in female offspring. Exposure to 5 ppm, but not 0.5 ppm, cadmium significantly enhanced HFD cardiac effects only in female mice, shown by worsened cardiac systolic and diastolic dysfunction (ejection fraction, mitral E-to-annular e' ratio), increased fibrosis (collagen, fibronectin, collagen1A1), hypertrophy (cardiomyocyte size, atrial natriuretic peptide, ß-myosin heavy chain), and inflammation (intercellular adhesion molecule-1, tumor necrosis factor-α, plasminogen activator inhibitor type 1), compared to the HFD group. These synergistic effects were associated with activation of the p38 mitogen-activated protein kinases (MAPK) signaling pathway and increased oxidative stress, shown by 3-nitrotyrosine and malondialdehyde, along with decreased metallothionein expression. These results suggest that whole-life 5 ppm cadmium exposure significantly increases the susceptibility of female offspring to HFD-induced cardiac remodeling and dysfunction. The underlying mechanism and potential intervention will be further explored in the future.

Early-Life Exposure to Low-Dose Cadmium Accelerates Diethylnitrosamine and Diet-Induced Liver Cancer.

Maternal exposure to cadmium causes obesity and metabolic changes in the offspring, including nonalcoholic fatty liver disease-like pathology. However, whether maternal cadmium exposure accelerates liver cancer in the offspring is unknown. This study investigated the impact of early-life exposure to cadmium on the incidence and potential mechanisms of hepatocellular carcinoma (HCC) in offspring subjected to postweaning HCC induction. HCC in C57BL/6J mice was induced by diethylnitrosamine (DEN) injection at weaning, followed by a long-term high-fat choline-deficient (HFCD) diet. Before weaning, liver cadmium levels were significantly higher in mice with early-life cadmium exposure than in those without cadmium exposure. However, by 26 and 29 weeks of age, hepatic cadmium fell to control levels, while a significant decrease was observed in copper and iron in the liver. Both male and female cadmium-exposed mice showed increased body weight compared to non-cadmium-treated mice. For females, early-life cadmium exposure also worsened insulin intolerance but did not significantly promote DEN/HFCD diet-induced liver tumors. In contrast, in male mice, early-life cadmium exposure enhanced liver cancer induction by DEN/HFCD with high incidence and larger liver tumors. The liver peritumor tissue of early-life cadmium-exposed mice exhibited greater inflammation and disruption of fatty acid metabolism, accompanied by higher malondialdehyde and lower esterified triglyceride levels compared to mice without cadmium exposure. These findings suggest that early-life exposure to low-dose cadmium accelerates liver cancer development induced by a DEN/HFCD in male mice, probably due to chronic lipotoxicity and inflammation caused by increased uptake but decreased consumption of fatty acids.

Mechanism and prevention strategy of a bidirectional relationship between heart failure and cancer (Review).

The relationship between cancer and heart failure has been extensively studied in the last decade. These studies have focused on describing heart injury caused by certain cancer treatments, including radiotherapy, chemotherapy and targeted therapy. Previous studies have demonstrated a higher incidence of cancer in patients with heart failure. Heart failure enhances an over-activation of the sympathetic nervous system and the renin-angiotensin-aldosterone system, and subsequently promotes cancer development. Other studies have found that heart failure and cancer both have a common pathological origin, flanked by chronic inflammation in certain organs. The present review aims to summarize and describe the recent discoveries, suggested mechanisms and relationships between heart failure and cancer. The current review provides more ideas on clinical prevention strategies according to the pathological mechanism involved.

Protective Mechanism of Humanin Against Oxidative Stress in Aging-Related Cardiovascular Diseases.

Physiological reactive oxygen species (ROS) are important regulators of intercellular signal transduction. Oxidative and antioxidation systems maintain a dynamic balance under physiological conditions. Increases in ROS levels destroy the dynamic balance, leading to oxidative stress damage. Oxidative stress is involved in the pathogenesis of aging-related cardiovascular diseases (ACVD), such as atherosclerosis, myocardial infarction, and heart failure, by contributing to apoptosis, hypertrophy, and fibrosis. Oxidative phosphorylation in mitochondria is the main source of ROS. Increasing evidence demonstrates the relationship between ACVD and humanin (HN), an endogenous peptide encoded by mitochondrial DNA. HN protects cardiomyocytes, endothelial cells, and fibroblasts from oxidative stress, highlighting its protective role in atherosclerosis, ischemia-reperfusion injury, and heart failure. Herein, we reviewed the signaling pathways associated with the HN effects on redox signals, including Kelch-like ECH-associated protein 1 (Keap1)/nuclear factor erythroid 2-related factor 2 (Nrf2), chaperone-mediated autophagy (CMA), c-jun NH2 terminal kinase (JNK)/p38 mitogen-activated protein kinase (p38 MAPK), adenosine monophosphate-activated protein kinase (AMPK), and phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)-Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3). Furthermore, we discussed the relationship among HN, redox signaling pathways, and ACVD. Finally, we propose that HN may be a candidate drug for ACVD.

Cardiac metallothionein overexpression rescues diabetic cardiomyopathy in Akt2-knockout mice.

To efficiently prevent diabetic cardiomyopathy (DCM), we have explored and confirmed that metallothionein (MT) prevents DCM by attenuating oxidative stress, and increasing expression of proteins associated with glucose metabolism. To determine whether Akt2 expression is critical to MT prevention of DCM, mice with either global Akt2 gene deletion (Akt2-KO), or cardiomyocyte-specific overexpressing MT gene (MT-TG) or both combined (MT-TG/Akt2-KO) were used. Akt2-KO mice exhibited symptoms of DCM (cardiac remodelling and dysfunction), and reduced expression of glycogen and glucose metabolism-related proteins, despite an increase in total Akt (t-Akt) phosphorylation. Cardiac MT overexpression in MT-TG/Akt2-KO mice prevented DCM and restored glucose metabolism-related proteins expression and baseline t-Akt phosphorylation. Furthermore, phosphorylation of ERK1/2 increased in the heart of MT-TG/Akt2-KO mice, compared with Akt2-KO mice. As ERK1/2 has been implicated in the regulation of glucose transport and metabolism this increase could potentially underlie MT protective effect in MT-TG/Akt2-KO mice. Therefore, these results show that although our previous work has shown that MT preserving Akt2 activity is sufficient to prevent DCM, in the absence of Akt2 MT may stimulate alternative or downstream pathways protecting from DCM in a type 2 model of diabetes, and that this protection may be associated with the ERK activation pathway.

Potential roles of mediator Complex Subunit 13 in Cardiac Diseases.

Mediator complex subunit 13 (MED13, previously known as THRAP1 and TRAP240) is a subunit of the cyclin-dependent kinase 8 (CDK8) kinase module in the eukaryotic mediator complex. MED13 has been known to play critical roles in cell cycle, development, and growth. The purpose of this review is to comprehensively discuss its newly identified potential roles in myocardial energy metabolism and non-metabolic cardiovascular diseases. Evidence indicates that cardiac MED13 mainly participates in the regulation of nuclear receptor signaling, which drives the transcription of genes involved in modulating cardiac and systemic energy homeostasis. MED13 is also associated with several pathological conditions, such as metabolic syndrome and thyroid disease-associated heart failure. Therefore, MED13 constitutes a potential therapeutic target for the regulation of metabolic disorders and other cardiovascular diseases.

The regulatory roles of p53 in cardiovascular health and disease.

Cardiovascular disease (CVD) remains the leading cause of mortality globally, so further investigation is required to identify its underlying mechanisms and potential targets for its prevention. The transcription factor p53 functions as a gatekeeper, regulating a myriad of genes to maintain normal cell functions. It has received a great deal of research attention as a tumor suppressor. In the past three decades, evidence has also shown a regulatory role for p53 in the heart. Basal p53 is essential for embryonic cardiac development; it is also necessary to maintain normal heart architecture and physiological function. In pathological cardiovascular circumstances, p53 expression is elevated in both patient samples and animal models. Elevated p53 plays a regulatory role via anti-angiogenesis, pro-programmed cell death, metabolism regulation, and cell cycle arrest regulation. This largely promotes the development of CVDs, particularly cardiac remodeling in the infarcted heart, hypertrophic cardiomyopathy, dilated cardiomyopathy, and diabetic cardiomyopathy. Roles for p53 have also been found in atherosclerosis and chemotherapy-induced cardiotoxicity. However, it has different roles in cardiomyocytes and non-myocytes, even in the same model. In this review, we describe the different effects of p53 in cardiovascular physiological and pathological conditions, in addition to potential CVD therapies targeting p53.

Monoamine oxidase inhibitors protect against coronary heart disease in rodent rat models: A pilot study.

The present study designed to investigate the effect of monoamine oxidase inhibitor in the rat model of Coronary heart disease (cardiac hypertrophy). A total of 40 male adult Wistar rats having body weight 300-400 gram were equally distributed in two groups (Test group: Rats with Angiotensin II + monoamine oxidase inhibitor (Befloxatone); Reference group: Rats with cardiac hypertrophy induced by Angiotensin II). Rat model of cardiac hypertrophy were induced by Angiotensin II. Effect of Befloxatone on cardiac hypertrophy was evaluated by electrocardiography, hemodynamic and histological assessment. Vital signs such as pulse rate, and blood pressure were measured. Echocardiographic related variable including ejection fraction were also assessed in both the groups. Also, expression of monoamine oxidase was analyzed using by real-time-PCR and Western blot analysis. In results, we found following 1) monoamine oxidase inhibitor treatment prevents Angiotensin II induced increase in level of ANP and ßeta-myosin, which are responsible for inducing cardiac hypertrophic responses; 2) monoamine oxidase inhibitor ameliorates Angiotensin II induced cell enlargement by reducing the surface area of cells; 3) monoamine oxidase inhibitor attenuates the hypertrophic response triggered by Angiotensin II; 4) monoamine oxidase inhibitor ameliorates increased heart rate and average arterial pressure induced by angiotensin II; 5) Overall finding suggested that monoamine oxidase inhibitor improves left ventricle hypertrophy and ejection fraction by inhibiting monoamine oxidase enzyme in heart. The finding of this study gives the new vision to cardiovascular researchers to develop anti- hypertrophy therapy based on monoamine oxidase inhibition.