Heavy Metal Exposure-Induced Cardiovascular Diseases: Molecular Mechanisms and Therapeutic Role of Antioxidants.

Globally, cardiovascular diseases (CVDs) are the main cause of mortality every year worldwide. CVD health is influenced by various health factors, such as blood pressure, cholesterol levels, and glucose control. The main risk factors include smoking, physical activity, food intake, and body mass index. Around 90% of CVDs could be prevented by controlling these risk factors. Heavy metals are indigenous to the environment of the earth. However, modern lifestyles have led to the exploitation of our environment by unconstrained use of heavy metals. Though heavy metals are essential components, they are hazardous to humans and living systems due to their persistent and non-degradable nature. The mainpurpose of this study is to provide a literature review on the mechanisms of heavy metals, particularly arsenic, lead, and cadmium, that cause cardiovascular diseases. The major mechanism by which heavy metals result in various modalities of cardiovascular disease is the generation of reactive species and the depletionof the antioxidant reserves inside the biological system. The generation of reactive species gradually leads to the activation of various signaling pathways, resulting in either apoptosis or unrestricted cell growth. These unfavorable conditions result in a state when there is an imbalance between reactive species generation and antioxidant activity. Both endogenously present antioxidants and dietary antioxidants are very much essential in regulating the redox potential of the body. They help in the detoxification and excretion of heavy metals and their metabolites in the biological system. Therefore, recognizing the role of heavy metals in cardiovascular health is crucial for developing preventive strategies and interventions aimed at mitigating their adverse effects on human health.

Atrazine Toxicity: The Possible Role of Natural Products for Effective Treatment.

There are various herbicides which were used in the agriculture industry. Atrazine (ATZ) is a chlorinated triazine herbicide that consists of a ring structure, known as the triazine ring, along with a chlorine atom and five nitrogen atoms. ATZ is a water-soluble herbicide, which makes it capable of easily infiltrating into majority of the aquatic ecosystems. There are reports of toxic effects of ATZ on different systems of the body but, unfortunately, majority of these scientific reports were documented in animals. The herbicide was reported to enter the body through various routes. The toxicity of the herbicide can cause deleterious effects on the respiratory, reproductive, endocrine, central nervous system, gastrointestinal, and urinary systems of the human body. Alarmingly, few studies in industrial workers showed ATZ exposure leading to cancer. We embarked on the present review to discuss the mechanism of action of ATZ toxicity for which there is no specific antidote or drug. Evidence-based published literature on the effective use of natural products such as lycopene, curcumin, Panax ginseng, Spirulina platensis, Fucoidans, vitamin C, soyabeans, quercetin, L-carnitine, Telfairia occidentalis, vitamin E, Garcinia kola, melatonin, selenium, Isatis indigotica, polyphenols, Acacia nilotica, and Zingiber officinale were discussed in detail. In the absence of any particular allopathic drug, the present review may open the doors for future drug design involving the natural products and their active compounds.

Kinase Inhibitors Involved in the Regulation of Autophagy: Molecular Concepts and Clinical Implications.

All cells and intracellular components are remodeled and recycled in order to replace the old and damaged cells. Autophagy is a process by which damaged, and unwanted cells are degraded in the lysosomes. There are three different types of autophagy: macroautophagy, microautophagy, and chaperone-mediated autophagy. Autophagy has an effect on adaptive and innate immunity, suppression of any tumour, and the elimination of various microbial pathogens. The process of autophagy has both positive and negative effects, and this pertains to any specific disease or its stage of progression. Autophagy involves various processes which are controlled by various signaling pathways, such as Jun N-terminal kinase, GSK3, ERK1, Leucine-rich repeat kinase 2, and PTEN-induced putative kinase 1 and parkin RBR E3. Protein kinases are also important for the regulation of autophagy as they regulate the process of autophagy either by activation or inhibition. The present review discusses the kinase catalyzed phosphorylated reactions, the kinase inhibitors, types of protein kinase inhibitors and their binding properties to protein kinase domains, the structures of active and inactive kinases, and the hydrophobic spine structures in active and inactive protein kinase domains. The intervention of autophagy by targeting specific kinases may form the mainstay of treatment of many diseases and lead the road to future drug discovery.

Natural Products in Mitigation of Bisphenol A Toxicity: Future Therapeutic Use.

Bisphenol A (BPA) is a ubiquitous environmental toxin with deleterious endocrine-disrupting effects. It is widely used in producing epoxy resins, polycarbonate plastics, and polyvinyl chloride plastics. Human beings are regularly exposed to BPA through inhalation, ingestion, and topical absorption routes. The prevalence of BPA exposure has considerably increased over the past decades. Previous research studies have found a plethora of evidence of BPA's harmful effects. Interestingly, even at a lower concentration, this industrial product was found to be harmful at cellular and tissue levels, affecting various body functions. A noble and possible treatment could be made plausible by using natural products (NPs). In this review, we highlight existing experimental evidence of NPs against BPA exposure-induced adverse effects, which involve the body's reproductive, neurological, hepatic, renal, cardiovascular, and endocrine systems. The review also focuses on the targeted signaling pathways of NPs involved in BPA-induced toxicity. Although potential molecular mechanisms underlying BPA-induced toxicity have been investigated, there is currently no specific targeted treatment for BPA-induced toxicity. Hence, natural products could be considered for future therapeutic use against adverse and harmful effects of BPA exposure.

Effects of constitutively active IKKß on cardiac development.

NF-κB is a major transcription factor regulating cell survival, organ development and inflammation, but its role in cardiac development has been inadequately explored. To examine this function, we generated mice in which IKKß, an essential kinase for NF-κB activation, was constitutively activated in embryonic cardiomyocytes. For this purpose, we used smooth muscle-22α (SM22α)-Cre mice, which are frequently used for gene recombination in embryonic cardiomyocytes. Embryonic hearts of SM22αCre-CA (constitutively active) IKKßflox/flox mice revealed remarkably thin, spongy and hypoplastic myocardium. In exploring the mechanism, we found that the expression of bone morphogenetic protein 10 (BMP10) and T-box transcription factor 20 (Tbx20), major regulators of cardiac development, was significantly downregulated and upregulated, respectively, in the SM22αCre-CAIKKßflox/flox mice. We also generated NK2 homeobox 5 (Nkx2.5) Cre-CAIKKßflox/wt mice since Nkx2.5 is also expressed in embryonic cardiomyocytes and confirmed that the changes in these genes were also observed. These results implicated that the activation of NF-κB affects cardiac development.

Role of Bisphenol A in Autophagy Modulation: Understanding the Molecular Concepts and Therapeutic Options.

Bisphenol A (4,4'-isopropylidenediphenol) is an organic compound commonly used in plastic bottles, packaging containers, beverages, and resin industry. The adverse effects of bisphenol A in various systems of the body have been studied. Autophagy is a lysosomal degradation process that leads to the regeneration of new cells. The role of bisphenol A in autophagy modulation involved in the pathogenesis of diseases is still debatable. A few research studies have shown bisphenol Ainduced adverse effects to be associated with autophagy dysregulation, while a few have shown the activation of autophagy to be mediated by bisphenol A. Such contrasting views make the subject more interesting and debatable. In the present review, we discuss the different steps of autophagy, genes involved, and the effect of autophagy modulation by bisphenol A on different systems of the body. We also discuss the methods for monitoring autophagy and the roles of drugs, such as chloroquine, verteporfin, and rapamycin, in autophagy. A proper understanding of the role of bisphenol A in the modulation of autophagy may be important for future treatment and drug discovery.

Maternal resveratrol supplementation ameliorates bisphenol A-induced atherosclerotic lesions formation in adult offspring ApoE-/- mice.

Current evidence suggests that intrauterine bisphenol A (BPA) exposure increases the risk of developing cardiovascular diseases in later stages of life. The beneficial effect of resveratrol (Rsv) on developmental programming of atherosclerosis lesions formation in offspring is seldom reported. Hence, we sought to study the effect of maternal Rsv in ameliorating perinatal BPA exposure-induced atherosclerosis lesions formation in adult offspring using the apolipoprotein E-deficient (ApoE-/-) mice model. The pregnant ApoE-/- mice were allocated into three groups: control, BPA, BPA + resveratrol (BPA + Rsv). The BPA group mice received BPA in their drinking water (1 µg/ml). BPA + Rsv group mice received BPA in their drinking water (1 µg/ml) and were treated orally with Rsv (20 mg kg-1 day-1). All the treatments were continued throughout the gestation and lactation period. Quantitative analysis of Sudan IV-stained aorta revealed a significantly increased area of atherosclerotic lesions in both female (p < 0.01) and male adult offspring mice (p < 0.01) in the BPA group. Supplementation with Rsv significantly reduced the BPA-induced atherosclerotic lesion development in the female offspring mice (p < 0.05). Transmission electron microscopy revealed the presence of a significantly high incidence of autophagic endothelial, smooth muscle, and macrophage cells in the aorta of BPA-exposed mice. Rsv treatment reduced the incidence of autophagic cells in BPA-exposed mice. In conclusion, maternal Rsv supplementation significantly prevents the BPA-induced atherosclerotic lesions formation in a sex-dependent manner potentially by acting as an autophagy modulator. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13205-021-03078-y.

Perinatal Exposure to Bisphenol A and Developmental Programming of the Cardiovascular Changes in the Offspring.

Bisphenol A (BPA) is an industrial ubiquitous compound, frequently used to produce synthetic polymers and epoxy resins. BPA is a well-recognized endocrine disruptor and xenoestrogen compound. Evidence from epidemiological and experimental studies suggests that perinatal BPA exposure (gestation and/or lactation) increases the risk of developing various diseases, including the cardiovascular system. Developmental programming refers to environmental insults during the critical window of development that affect the structure and physiology of body systems, causing permanent changes in later stages. BPA influences the developmental programming of non-communicable diseases in the offspring. In the present review, we discuss the developmental programming of cardiovascular diseases related to perinatal exposure to BPA, supported by epidemiological and experimental evidence from published literature. The majority of the reported studies found a positive association between perinatal BPA exposure and adverse cardiovascular repercussions in the fetal, neonatal, and adulthood stages. The possible underlying mechanisms include epigenetic modifications of genes involved in cardiac muscle development, autonomic tone, collagenous and non-collagenous extracellular matrix, cardiac remodeling and calcium homeostasis, and mitochondrial energy metabolism. Epigenetics can modify the outcome of any disease. Hence, in the present review, we also discuss the role of epigenetics in preventing cardiovascular diseases following perinatal exposure to BPA. We also highlight how future treatment and drug delivery related to cardiovascular involvement could be based on epigenetic markers.

Improvement of insulin signalling rescues inflammatory cardiac dysfunction.

Inflammation resulting from virus infection is the cause of myocarditis; however, the precise mechanism by which inflammation induces cardiac dysfunction is still unclear. In this study, we investigated the contribution of insulin signalling to inflammatory cardiac dysfunction induced by the activation of signalling by NF-κB, a major transcriptional factor regulating inflammation. We generated mice constitutively overexpressing kinase-active IKK-ß, an essential kinase for NF-κB activation, in cardiomyocytes (KA mice). KA mice demonstrated poor survival and significant cardiac dysfunction with remarkable dilation. Histologically, KA hearts revealed increased cardiac apoptosis and fibrosis and the enhanced recruitment of immune cells. By molecular analysis, we observed the increased phosphorylation of IRS-1, indicating the suppression of insulin signalling in KA hearts. To evaluate the contribution of insulin signalling to cardiac dysfunction in KA hearts, we generated mice with cardiac-specific suppression of phosphatase and tensin homologue 10 (PTEN), a negative regulator of insulin signalling, in the KA mouse background (KA-PTEN). The suppression of PTEN successfully improved insulin signalling in KA-PTEN hearts, and interestingly, KA-PTEN mice showed significantly improved cardiac function and survival. These results indicated that impaired insulin signalling underlies the mechanism involved in inflammation-induced cardiac dysfunction, which suggests that it may be a target for the treatment of myocarditis.

Deletion of IκB-Kinase ß in Smooth Muscle Cells Induces Vascular Calcification Through ß-Catenin-Runt-Related Transcription Factor 2 Signaling.

BACKGROUND: Vascular calcification was previously considered as an advanced phase of atherosclerosis; however, recent studies have indicated that such calcification can appear in different situations. Nevertheless, there has been a lack of mechanistic insight to explain the difference. For example, the roles of nuclear factor-κB, a major regulator of inflammation, in vascular calcification are poorly explored, although its roles in atherosclerosis were well documented. Herein, we investigated the roles of nuclear factor-κB signaling in vascular calcification. METHODS AND RESULTS: We produced mice with deletion of IKKß, an essential kinase for nuclear factor-κB activation, in vascular smooth muscle cells (VSMCs; KO mice) and subjected them to the CaCl2-induced aorta injury model. Unexpectedly, KO mice showed more calcification of the aorta than their wild-type littermates, despite the former's suppressed nuclear factor-κB activity. Cultured VSMCs from the aorta of KO mice also showed significant calcification in vitro. In the molecular analysis, we found that Runt-related transcription factor 2, a transcriptional factor accelerating bone formation, was upregulated in cultured VSMCs from KO mice, and its regulator ß-catenin was more activated with suppressed ubiquitination in KO VSMCs. Furthermore, we examined VSMCs from mice in which kinase-active or kinase-dead IKKß was overexpressed in VSMCs. We found that kinase-independent function of IKKß is involved in suppression of calcification via inactivation of ß-catenin, which leads to suppression of Runt-related transcription factor 2 and osteoblast marker genes. CONCLUSIONS: IKKß negatively regulates VSMC calcification through ß-catenin-Runt-related transcription factor 2 signaling, which revealed a novel function of IKKß on vascular calcification.