Cytosolic free Zn⁺ level ([Zn⁺]) is tightly regulated by Zn⁺ transporters, under both physiological and pathological conditions. At the cellular level, dysregulated free Zn⁺ levels have been linked to metabolic and cardiovascular diseases, primarily through their association with various Zn⁺ transporters. However, the role and localization of ZnT6 in cardiomyocytes remain unclear.
View Article and Find Full Text PDFBackground: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are known for their benefits in conditions like cardiovascular diseases in type 2 diabetes and obesity. They also show promise for aging-related conditions with minimal side effects. However, their impact on cardiovascular risk is still debated.
View Article and Find Full Text PDFIn the heart, ion channels generate electrical currents that signal muscle contraction through changes in intracellular calcium concentration, i.e., [Ca].
View Article and Find Full Text PDFCardiac conduction abnormalities are disorders in metabolic syndrome (MetS), however, their mechanisms are unknown. Although ventricular arrhythmia reflects the changes in QT-interval of electrocardiograms associated with the changes in cardiomyocyte action potential durations (APDs), recent studies emphasize role of intercellular crosstalk between cardiomyocytes and nonmyocytes via passive (electrotonic)-conduction. Therefore, considering the possible increase in intercellular interactions of nonmyocytes with cardiomyocytes, we hypothesized an early-cardiac-remodeling characterized by short QT-interval via contributions and modulations of changes by nonmyocytes to the ventricular APs in an early-stage MetS hearts.
View Article and Find Full Text PDFDoxorubicin (DOXO) induces marked cardiotoxicity, though increased oxidative stress while there are some documents related with cardioprotective effects of some antioxidants against organ-toxicity during cancer treatment. Although magnolia bark has some antioxidant-like effects, its action in DOXO-induced heart dysfunction has not be shown clearly. Therefore, here, we aimed to investigate the cardioprotective action of a magnolia bark extract with active component magnolol and honokiol complex (MAHOC; 100 mg/kg) in DOXO-treated rat hearts.
View Article and Find Full Text PDFCalmodulin (CaM) plays critical roles in cardiomyocytes, regulating Na+ (NaV) and L-type Ca2+ channels (LTCCs). LTCC dysregulation by mutant CaMs has been implicated in action potential duration (APD) prolongation and arrhythmogenic long QT (LQT) syndrome. Intriguingly, D96V-CaM prolongs APD more than other LQT-associated CaMs despite inducing comparable levels of LTCC dysfunction, suggesting dysregulation of other depolarizing channels.
View Article and Find Full Text PDFThe correlation between long-QT and connexin 43 (Cx43) status and localization in elderly rats was determined to demonstrate a correlation between insulin resistance (I-R), ischemia-reperfusion, aging, and heart dysfunction. Male Wistar rats are grouped as 24-month-old rats (Aged-group), those with metabolic syndrome (8 months old; MetS-group), or controls (8 months old; Con-group). Both experimental groups have long-QT and low heart rate.
View Article and Find Full Text PDFRecent studies discuss the evidence of lesser degrees of hyperglycemia contribution to cardiovascular disease (CVD) than impaired glucose tolerance. Indeed, the biggest risk for CVD seems to shift to glucose intolerance in humans with insulin resistance. Although there is a connection between abnormal insulin signaling and heart dysfunction in diabetics, there is also a relation between cardiac insulin resistance and aging heart failure (HF).
View Article and Find Full Text PDFPurpose: Metabolic syndrome (MetS) became a tremendous public health burden in the last decades. Store-operated calcium entry (SOCE) is a unique mechanism that causes a calcium influx, which is triggered by calcium store depletion. MetS-induced alterations in cardiac calcium signaling, especially in SOCE are still unclear.
View Article and Find Full Text PDFInsufficient-heart function is associated with myocardial insulin resistance in the elderly, particularly associated with long-QT, in a dependency on dysfunctional KCNQ1/KCNE1-channels. So, we aimed to examine the contribution of alterations in KCNQ1/KCNE1-current (I ) to the aging-related remodeling of the heart as well as the role of insulin treatment on I in the aged rats. Prolonged late-phase action potential (AP) repolarization of ventricular cardiomyocytes from insulin-resistant 24-month-old rats was significantly reversed by in vitro treatment of insulin or PKG inhibitor (in vivo, as well) via recovery in depressed I .
View Article and Find Full Text PDFThe matrix metalloproteinases (MMPs) contribute to matrix remodeling in diabetes via tissue degradation; however, their contributions can be different depending on the pathology. For instance, MMPs are elevated in acute stress hyperglycemia, whereas they can be degraded in chronic hyperglycemia. Since studies emphasize the possible cardioprotective effect of ticagrelor (Tica) beyond its antiplatelet action, we aimed to examine whether Tica treatment can reverse the depressed heart function of metabolic syndrome (MetS) rats via affecting the expression levels of MMPs.
View Article and Find Full Text PDFMetabolic syndrome (MetS) is associated with additional cardiovascular risk in mammalians while there are relationships between hyperglycemia-associated cardiovascular dysfunction and increased platelet P2Y12 receptor activation. Although P2Y12 receptor antagonist ticagrelor (Tica) plays roles in reduction of cardiovascular events, its beneficial mechanism remains poorly understood. Therefore, we aimed to clarify whether Tica can exert a direct protective effect in ventricular cardiomyocytes from high-carbohydrate diet-induced MetS rats, at least, through affecting sarcoplasmic reticulum (SR)-mitochondria (Mit) miscommunication.
View Article and Find Full Text PDFCardiovasc Toxicol
April 2021
Consumption of illicit pharmaceutical products containing sibutramine has been reported to cause cardiovascular toxicity problems. This study aimed to demonstrate the toxicity profile of sibutramine, and thereby provide important implications for the development of more effective strategies in both clinical approaches and drug design studies. Action potentials (APs) were determined from freshly isolated ventricular cardiomyocytes with whole-cell configuration of current clamp as online.
View Article and Find Full Text PDFThe prevalence of death from cardiovascular disease is significantly higher in elderly populations; the underlying factors that contribute to the age-associated decline in cardiac performance are poorly understood. Herein, we identify the involvement of sodium/glucose co-transporter gene (SGLT2) in disrupted cellular Ca -homeostasis, and mitochondrial dysfunction in age-associated cardiac dysfunction. In contrast to younger rats (6-month of age), older rats (24-month of age) exhibited severe cardiac ultrastructural defects, including deformed, fragmented mitochondria with high electron densities.
View Article and Find Full Text PDFBackground Atrial fibrillation (AF) is a comorbidity associated with heart failure and catecholaminergic polymorphic ventricular tachycardia. Despite the Ca-dependent nature of both of these pathologies, AF often responds to Na channel blockers. We investigated how targeting interdependent Na/Ca dysregulation might prevent focal activity and control AF.
View Article and Find Full Text PDFThe death prevalence from cardiovascular disease is significantly high in elderly-populations, while mitochondrial-aging plays an important in abnormal function of vital organs through high mitochondrial ROS production. Mitochondria have a unique mode of action by providing ATP production and modulating the cytosolic Ca-signaling and maintain the redox status of cardiomyocytes. There is an aging-associated impairment in oxidative phosphorylation which causes a marked dysregulation of mitochondrial biogenesis.
View Article and Find Full Text PDFTicagrelor, a PY-receptor inhibitor, and a non-thienopyridine agent are used to treat diabetic patients via its effects on off-target mechanisms. However, the exact sub-cellular mechanisms by which ticagrelor exerts those effects remains to be elucidated. Accordingly, the present study aimed to examine whether ticagrelor influences directly the cardiomyocytes function under insulin resistance through affecting mitochondria-sarco(endo)plasmic reticulum (SER) cross-talk.
View Article and Find Full Text PDFObesity-induced insulin resistance and type 2 diabetes mellitus can ultimately result in various complications, including diabetic cardiomyopathy. In this case, cardiac dysfunction is characterized by metabolic disturbances such as impaired glucose oxidation and an increased reliance on fatty acid (FA) oxidation. Mitochondrial dysfunction has often been associated with the altered metabolic function in the diabetic heart, and may result from FA-induced lipotoxicity and uncoupling of oxidative phosphorylation.
View Article and Find Full Text PDFAging is an important risk factor for cardiac dysfunction. Heart during aging exhibits a depressed mechanical activity, at least, through mitochondria-originated increases in ROS. Previously, we also have shown a close relationship between increased ROS and cellular intracellular free Zn ([Zn]) in cardiomyocytes under pathological conditions as well as the contribution of some re-expressed levels of Zn-transporters for redistribution of [Zn] among suborganelles.
View Article and Find Full Text PDFAzoramide is identified as a new compound with the dual properties for the improvement of ER-folding capacity in various cells as well as for the treatment of T2DM. Although the effect of azoramide in glucose-homeostasis in mammalians is not known very well, a limited number of experimental studies showed that it could improve the insulin sensitivity in genetically obese mice. Therefore, here, we aimed to investigate the direct effect of azoramide on insulin signaling in insulin-resistant (IR) cardiomyocytes using IR-modelled ventricular cardiomyocytes.
View Article and Find Full Text PDFRole of β -AR dysregulation, as either cardio-conserving or cardio-disrupting mediator, remains unknown yet. Therefore, we examined the molecular mechanism of β -AR activation in depressed myocardial contractility using a specific agonist CL316243 or using β -AR overexpressed cardiomyocytes. Since it has been previously shown a possible correlation between increased cellular free Zn ([Zn ] ) and depressed cardiac contractility, we first demonstrated a relation between β -AR activation and increased [Zn ] , parallel to the significant depolarization in mitochondrial membrane potential in rat ventricular cardiomyocytes.
View Article and Find Full Text PDFBackground: Metabolic syndrome (MetS) is a prevalent risk factor for cardiac dysfunction. Although SGLT2-inhibitors have important cardioprotective effects in hyperglycemia, their underlying mechanisms are complex and not completely understood. Therefore, we examined mechanisms of a SGLT2-inhibitor dapagliflozin (DAPA)-related cardioprotection in overweight insulin-resistant MetS-rats comparison with insulin (INSU), behind its glucose-lowering effect.
View Article and Find Full Text PDFSodium-glucose cotransporter 2 (SGLT2) inhibitors showed significant effects in patients with diabetes or metabolic syndrome (MetS) with high cardiovascular risk. Although the increased intracellular Zn level ([Zn]), oxidative stress, and altered cardiac matrix metalloproteinases (MMPs) in diabetic cardiomyopathy can intersect with different signaling pathways, the exact mechanisms are not known yet. Since either MMPs or SGLT2 have important roles in cardiac-fibrosis under hyperglycemia, we aimed to examine the role of SGLT2 inhibitor dapagliflozin (DAP) on cardiac Zn-transporters responsible for [Zn]-regulation, comparison to insulin (INS), together with MMP levels and systemic oxidative stress status in MetS-rats.
View Article and Find Full Text PDFAging in humans represents declining in cardio-protective systems, however its mechanisms are not known yet. We aimed to analyse how aging affects key mechanisms responsible for contractile dysfunction via comparing the improperly synchrony between electrical and mechanical activities in male aged-rats (24-month old) comparison to those of adult-rats (6-month old). We determined significantly increased systemic oxidative stress with decreased antioxidant capacity, clear insulin resistance and hypertrophy in aged-rats with normal fasting blood glucose.
View Article and Find Full Text PDFIntracellular labile (free) Zn-level ([Zn]) is low and increases markedly under pathophysiological conditions in cardiomyocytes. High [Zn] is associated with alterations in excitability and ionic-conductances while exact mechanisms are not clarified yet. Therefore, we examined the elevated-[Zn] on some sarcolemmal ionic-mechanisms, which can mediate cardiomyocyte dysfunction.
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