Trastuzumab cardiotoxicity and drug cardioprotection in healthy and cardiac dysfunction mouse models.

Pre-existing cardiovascular disease is a recognised risk factor for cardiotoxicity in HER2-targeted therapies such as trastuzumab (TRZ), but few studies have addressed the impact of TRZ and the effects of cardioprotective drugs in pre-existing cardiac issues. This study examines the impact of TRZ-induced cardiotoxicity in pre-existing cardiac conditions and the effects of captopril and bisoprolol in mouse models with varying degrees of cardiac impairment. Adult mice models with and without baseline cardiac dysfunction ̶ healthy mice (WT), transgenic mice with cardiac hyperaldosteronism (AS) and mice with cardiac dysfunction (AS+ISO) ̶ were randomised to receive placebo, TRZ alone (6 mg/kg/week for 4 weeks), or TRZ administered concomitantly with a cardioprotective therapy based on captopril (ACEi, 20 mg/kg) and bisoprolol (BB, 5 mg/kg) (TRZ+ACEi/BB).

Thyroid Hormone Signaling in Retinal Development and Function: Implications for Diabetic Retinopathy and Age-Related Macular Degeneration.

Thyroid Hormones (THs) play a central role in the development, cell growth, differentiation, and metabolic homeostasis of neurosensory systems, including the retina. The coordinated activity of various components of TH signaling, such as TH receptors (THRs) and the TH processing enzymes deiodinases 2 and 3 (DIO2, DIO3), is required for proper retinal maturation and function of the adult photoreceptors, Müller glial cells, and pigmented epithelial cells. Alterations of TH homeostasis, as observed both in frank or subclinical thyroid disorders, have been associated with sight-threatening diseases leading to irreversible vision loss i.

Effects of sacubitril-valsartan on remodelling, fibrosis and mitochondria in a murine model of isoproterenol-induced left ventricular dysfunction.

Background: Sacubitril/valsartan has been demonstrated to promote left ventricular (LV) reverse remodelling and improve outcomes in patients with heart failure (HF) with reduced ejection fraction (EF). Its molecular and tissue effects have not been fully elucidated yet, due to the paucity of preclinical studies, mostly based on ischaemic models. We aimed to evaluate the effects of sacubitril/valsartan on LV remodelling, myocardial fibrosis and mitochondrial biology in a murine model of non-ischaemic LV dysfunction.

Targeting the Translocator Protein (18 kDa) in Cardiac Diseases: State of the Art and Future Opportunities.

Mitochondria dysfunctions are typical hallmarks of cardiac disorders (CDs). The multiple tasks of this energy-producing organelle are well documented, but its pathophysiologic involvement in several manifestations of heart diseases, such as altered electromechanical coupling, excitability, and arrhythmias, is still under investigation. The human 18 kDa translocator protein (TSPO) is a protein located on the outer mitochondrial membrane whose expression is altered in different pathological conditions, including CDs, making it an attractive therapeutic and diagnostic target.

Lithium Treatment Induces Cardiac Dysfunction in Mice.

Lithium (Li) salts are commonly used as medications for bipolar disorders. In addition to its therapeutic value, Li is also being increasingly used as a battery component in modern electronic devices. Concerns about its toxicity and negative impact on the heart have recently been raised.

Dietary Patterns, Gut Microbiota Remodeling, and Cardiometabolic Disease.

The cardiovascular and metabolic disorders, collectively known as cardiometabolic disease (CMD), are high morbidity and mortality pathologies associated with lower quality of life and increasing health-care costs. The influence of the gut microbiota (GM) in dictating the interpersonal variability in CMD susceptibility, progression and treatment response is beginning to be deciphered, as is the mutualistic relation established between the GM and diet. In particular, dietary factors emerge as pivotal determinants shaping the architecture and function of resident microorganisms in the human gut.

Activated fibroblasts in cardiac and cancer fibrosis: An overview of analogies and new potential therapeutic options.

Heart disease and cancer are two major causes of morbidity and mortality in the industrialized countries, and their increasingly recognized connections are shifting the focus from single disease studies to an interdisciplinary approach. Fibroblast-mediated intercellular crosstalk is critically involved in the evolution of both pathologies. In healthy myocardium and in non-cancerous conditions, resident fibroblasts are the main cell source for synthesis of the extracellular matrix (ECM) and important sentinels of tissue integrity.

Role of miR-133/Dio3 Axis in the T3-Dependent Modulation of Cardiac mitoK-ATP Expression.

The opening of the ATP-sensitive mitochondrial potassium channel (mitok-ATP) is a common goal of cardioprotective strategies in the setting of acute and chronic myocardial disease. The biologically active thyroid hormone (TH), 3-5-3-triiodothyronine (T3), has been indicated as a potential activator of mitoK-ATP but the underlying mechanisms are still elusive. Here we describe a novel role of T3 in the transcriptional regulation of mitoK and mitoSur, the recently identified molecular constituents of the channel.

Mitochondria-Targeted Drug Delivery in Cardiovascular Disease: A Long Road to Nano-Cardio Medicine.

Cardiovascular disease (CVD) represents a major threat for human health. The available preventive and treatment interventions are insufficient to revert the underlying pathological processes, which underscores the urgency of alternative approaches. Mitochondria dysfunction plays a key role in the etiopathogenesis of CVD and is regarded as an intriguing target for the development of innovative therapies.

T3 Critically Affects the Mhrt/Brg1 Axis to Regulate the Cardiac MHC Switch: Role of an Epigenetic Cross-Talk.

The LncRNA my-heart (Mhrt) and the chromatin remodeler Brg1 inhibit each other to respectively prevent or favor the maladaptive α-myosin-heavy-chain (Myh6) to β-myosin-heavy-chain (Myh7) switch, so their balance crucially guides the outcome of cardiac remodeling under stress conditions. Even though triiodothyronine (T3) has long been recognized as a critical regulator of the cardiac Myh isoform composition, its role as a modulator of the Mhrt/Brg1 axis is still unexplored. Here the effect of T3 on the Mhrt/Brg1 regulatory circuit has been analyzed in relation with chromatin remodeling and previously identified T3-dependent miRNAs.

Myo-inositol and d-chiro-inositol oral supplementation ameliorate cardiac dysfunction and remodeling in a mouse model of diet-induced obesity.

Obesity is an independent risk factor to develop cardiac functional and structural impairments. Here, we investigated the effects of supplementation of inositols on the electrical, structural, and functional cardiac alterations in the mouse model of high fat diet (HFD) induced obesity. Three groups of C57BL6 mice (n = 16 each) were studied: j) HFD feeding; jj) HFD feeding + inositols from week 9 to 13; jjj) standard diet feeding.

Murine model of left ventricular diastolic dysfunction and electro-mechanical uncoupling following high-fat diet.

Background/objectives: It is well established that obesity is an independent risk factor for cardiac death. In particular various cardiac alterations have been described in obese patients such as long QT on ECG, impaired diastolic filling of the left ventricle (LV), and all-type arrhythmias. In the present study, the above alterations were all reproduced in a mouse model of fat diet-induced obesity.

Angiopoietin 2 signal complexity in cardiovascular disease and cancer.

The angiopoietin signal transduction system is a complex of vascular-specific kinase pathways that plays a crucial role in angiogenesis and maintenance of vascular homeostasis. Angiopoietin1 (Ang1) and 2 (Ang2), the ligand proteins of the pathway, belong to a family of glycoproteins that signal primarily through the transmembrane Tyrosine-kinase-2 receptor. Despite a considerable sequence homology, Ang1 and Ang2 manifest antagonistic effects in pathophysiological conditions.

Novel Insight Into the Epigenetic and Post-transcriptional Control of Cardiac Gene Expression by Thyroid Hormone.

Thyroid hormone (TH) signaling is critically involved in the regulation of cardiovascular physiology. Even mild reductions of myocardial TH levels, as occur in hypothyroidism or low T3 state conditions, are thought to play a role in the progression of cardiac disorders. Due to recent advances in molecular mechanisms underlying TH action, it is now accepted that TH-dependent modulation of gene expression is achieved at multiple transcriptional and post-transcriptional levels and involves the cooperation of many processes.

Protective Effects of Euthyroidism Restoration on Mitochondria Function and Quality Control in Cardiac Pathophysiology.

Mitochondrial dysfunctions are major contributors to heart disease onset and progression. Under ischemic injuries or cardiac overload, mitochondrial-derived oxidative stress, Ca dis-homeostasis, and inflammation initiate cross-talking vicious cycles leading to defects of mitochondrial DNA, lipids, and proteins, concurrently resulting in fatal energy crisis and cell loss. Blunting such noxious stimuli and preserving mitochondrial homeostasis are essential to cell survival.

Integrative analysis of differentially expressed genes and miRNAs predicts complex T3-mediated protective circuits in a rat model of cardiac ischemia reperfusion.

Thyroid hormone (T3) dyshomeostasis in the cardiac ischemia-reperfusion (IR) setting negatively impacts on mitochondria function and extracellular matrix remodeling. The modulation of cardiac miRNAs may represent the underlying molecular mechanisms, but a systems biology perspective investigating this critical issue in depth is still lacking. A rat model of myocardial IR, with or without an early short-term T3-replacement, was used to predict putative T3-dependent miRNA-gene interactions targeted to mitochondria quality control and wound healing repair.

T3 enhances Ang2 in rat aorta in myocardial I/R: comparison with left ventricle.

Angiogenesis is important for recovery after tissue damage in myocardial ischemia/reperfusion, and tri-iodothyronine (T3) has documented effects on angiogenesis. The angiopoietins 1/2 and tyrosine kinase receptor represent an essential system in angiogenesis controlling endothelial cell survival and vascular maturation. Recently, in a 3-day ischemia/reperfusion rat model, the infusion of a low dose of T3 improved the post-ischemic recovery of cardiac function.

Cardioprotection and thyroid hormones.

The evolution of cardiac disease after an acute ischemic event depends on a complex and dynamic network of mechanisms alternating from ischemic damage due to acute coronary occlusion to reperfusion injury due to the adverse effects of coronary revascularization till post-ischemic remodeling. Cardioprotection is a new purpose of the therapeutic interventions in cardiology with the goal to reduce infarct size and thus prevent the progression toward heart failure after an acute ischemic event. In a complex biological system such as the human one, an effective cardioprotective strategy should diachronically target the network of cross-talking pathways underlying the disease progression.

Early and Short-term Triiodothyronine Supplementation Prevents Adverse Postischemic Cardiac Remodeling: Role of Transforming Growth Factor-β1 and Antifibrotic miRNA Signaling.

Activation of transforming growth factor (TGF)-β1 signaling in the ischemia/reperfusion (I/R) injured myocardium leads to dysregulation of miR-29-30-133, favoring the profibrotic process that leads to adverse cardiac remodeling (CR). We have previously shown that timely correction of the postischemic low-T3 syndrome (Low-T3S) exerts antifibrotic effects, but the underlying molecular players are still unknown. Here we hypothesize that a prompt, short-term infusion of T3 in a rat model of post I/R Low-T3S could hamper the early activation of the TGFβ1-dependent profibrotic cascade to confer long-lasting cardioprotection against adverse CR.

Low T3 State Is Correlated with Cardiac Mitochondrial Impairments after Ischemia Reperfusion Injury: Evidence from a Proteomic Approach.

Mitochondria are major determinants of cell fate in ischemia/reperfusion injury (IR) and common effectors of cardio-protective strategies in cardiac ischemic disease. Thyroid hormone homeostasis critically affects mitochondrial function and energy production. Since a low T3 state (LT3S) is frequently observed in the post infarction setting, the study was aimed to investigate the relationship between 72 h post IR T3 levels and both the cardiac function and the mitochondrial proteome in a rat model of IR.

Mitochondria as key targets of cardioprotection in cardiac ischemic disease: role of thyroid hormone triiodothyronine.

Ischemic heart disease is the major cause of mortality and morbidity worldwide. Early reperfusion after acute myocardial ischemia has reduced short-term mortality, but it is also responsible for additional myocardial damage, which in the long run favors adverse cardiac remodeling and heart failure evolution. A growing body of experimental and clinical evidence show that the mitochondrion is an essential end effector of ischemia/ reperfusion injury and a major trigger of cell death in the acute ischemic phase (up to 48-72 h after the insult), the subacute phase (from 72 h to 7-10 days) and chronic stage (from 10-14 days to one month after the insult).

Triiodothyronine prevents cardiac ischemia/reperfusion mitochondrial impairment and cell loss by regulating miR30a/p53 axis.

Mitochondrial dysfunctions critically affect cardiomyocyte survival during ischemia/reperfusion (I/R) injury. In this scenario p53 activates multiple signaling pathways that impair cardiac mitochondria and promote cell death. p53 is a validated target of miR-30 whose levels fall under ischemic conditions.