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.e., diabetic retinopathy (DR), and age-related macular degeneration (AMD). Although observational studies do not allow causal inference, emerging data from preclinical models suggest a possible correlation between TH signaling imbalance and the development of retina disease. In this review, we analyze the most important features of TH signaling relevant to retinal development and function and its possible implication in DR and AMD etiology. A better understanding of TH pathways in these pathological settings might help identify novel targets and therapeutic strategies for the prevention and management of retinal disease.

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. METHODS: Adult transgenic male mice with cardiac-specific hyperaldosteronism (AS mice) received subcutaneous isoproterenol injections to induce LV systolic dysfunction. After 7 days, mice were randomized to a 2-week treatment with saline (ISO-AS n = 15), valsartan (ISO + V n = 12) or sacubitril/valsartan (ISO + S/V n = 12). Echocardiography was performed at baseline, at day 7, and after each of the 2 weeks of treatment. After sacrifice at day 21, histological and immunochemical assays were performed. A control group of AS mice was also obtained (Ctrl-AS n = 8). RESULTS: Treatment with sacubitril/valsartan, but not with valsartan, induced a significant improvement in LVEF (p = 0.009 vs ISO-AS) and fractional shortening (p = 0.032 vs ISO-AS) after 2- week treatment. In both ISO + V and ISO + S/V groups, a trend toward reduction of the cardiac collagen 1/3 expression ratio was detected. ISO + V and ISO + S/V groups showed a significant recovery of mitochondrial morphology and inner membrane function meant for oxidative phosphorylation. CONCLUSION: In a murine model of non-ischaemic HF, sacubitril/valsartan proved to have beneficial effects on LV systolic function, and on cardiac energetics, by improving mitochondrial activity.

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. Currently, only a few TSPO ligands are employed in CDs and cardiac imaging. In this Perspective, we report an overview of the emerging role of TSPO at the heart level, focusing on the recent literature concerning the development of TSPO ligands used for fighting and imaging heart-related disease conditions. Accordingly, targeting TSPO might represent a successful strategy to achieve novel therapeutic and diagnostic strategies to unravel the fundamental mechanisms and to provide solutions to still unanswered questions in CDs.

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. We investigated the effects of long-term Li treatment on the heart, liver, and kidney in mice. Sixteen C57BL/6J mice were randomly assigned to receive oral administration of Li carbonate (n = 8) or act as a control group (n = 8) for 12 weeks. We evaluated the cardiac electrical activity, morphology and function, and pathways contributing to remodelling. We assessed the multi-organ toxicity using histopathology techniques in the heart, liver, and kidney. Our findings suggest that mice receiving Li had impaired systolic function and ventricular repolarisation and were more susceptible to arrhythmias under adrenergic stimulation. The Li treatment caused an increase in the cardiomyocytes' size, the modulation of the extracellular signal-regulated kinase (ERK) pathway, along with some minor tissue damage. Our findings revealed a cardiotoxic effect of Li at therapeutic dosage, along with some histopathological alterations in the liver and kidney. In addition, our study suggests that our model could be used to test potential treatments for Li-induced cardiotoxicity.

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. In turn, intestinal microbes influence the absorption, metabolism, and storage of ingested nutrients, with potentially profound effects on host physiology. Herein, we present an updated overview on major effects of dietary components on the GM, highlighting the beneficial and detrimental consequences of diet-microbiota crosstalk in the setting of CMD. We also discuss the promises and challenges of integrating microbiome data in dietary planning aimed at restraining CMD onset and progression with a more personalized nutritional approach.

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. In the setting of myocardial disease or cancer, quiescent fibroblasts activate, respectively, into myofibroblasts (myoFbs) and cancer-associated fibroblasts (CAFs), characterized by increased production of contractile proteins, and by a highly proliferative and secretory phenotype. Although the initial activation of myoFbs/CAFs is an adaptive process to repair the damaged tissue, massive deposition of ECM proteins leads to maladaptive cardiac or cancer fibrosis, a recognized marker of adverse outcome. A better understanding of the key mechanisms orchestrating fibroblast hyperactivity may help developing innovative therapeutic options to restrain myocardial or tumor stiffness and improve patient prognosis. Albeit still unappreciated, the dynamic transition of myocardial and tumor fibroblasts into myoFbs and CAFs shares several common triggers and signaling pathways relevant to TGF-ß dependent cascade, metabolic reprogramming, mechanotransduction, secretory properties, and epigenetic regulation, which might lay the foundation for future antifibrotic intervention. Therefore, the aim of this review is to highlight emerging analogies in the molecular signature underlying myoFbs and CAFs activation with the purpose of identifying novel prognostic/diagnostic biomarkers, and to elucidate the potential of drug repositioning strategies to mitigate cardiac/cancer fibrosis.

Gut Microbiota and Sex Hormones: Crosstalking Players in Cardiometabolic and Cardiovascular Disease.

The available evidence indicates a close connection between gut microbiota (GM) disturbance and increased risk of cardiometabolic (CM) disorders and cardiovascular (CV) disease. One major objective of this narrative review is to discuss the key contribution of dietary regimen in determining the GM biodiversity and the implications of GM dysbiosis for the overall health of the CV system. In particular, emerging molecular pathways are presented, linking microbiota-derived signals to the local activation of the immune system as the driver of a systemic proinflammatory state and permissive condition for the onset and progression of CM and CV disease. We further outline how the cross-talk between sex hormones and GM impacts disease susceptibility, thereby offering a mechanistic insight into sexual dimorphism observed in CVD. A better understanding of these relationships could help unravel novel disease targets and pave the way to the development of innovative, low-risk therapeutic strategies based on diet interventions, GM manipulation, and sex hormone analogues.

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. To mimic human ischemic heart damage, we used a rat model of a low T3 state as the outcome of a myocardial ischemia/reperfusion event, and neonatal rat cardiomyocytes (NRCM) challenged with hypoxia or H2O2. Either in the in vivo or in vitro models, T3 administration to recover the physiological concentrations was able to restore the expression level of both the channel subunits, which were found to be downregulated under the stress conditions. Furthermore, the T3-mediated transcriptional activation of mitoK-ATP in the myocardium and NRCM was associated with the repression of the TH-inactivating enzyme, deiodinase 3 (Dio3), and an up-regulation of the T3-responsive miR-133a-3p. Mechanistically, the loss and gain of function experiments and reporter gene assays performed in NRCM, have revealed a new regulatory axis whereby the silencing of Dio3 under the control of miR-133a-3p drives the T3-dependent modulation of cardiac mitoK and mitoSur transcription.

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. Oxidative stress, mitochondrial permeability transition pore opening, and excessive fission are major noxious pathways amenable to drug therapy. Thanks to the advancements of nanotechnology research, several mitochondria-targeted drug delivery systems (DDS) have been optimized with improved pharmacokinetic and biocompatibility, and lower toxicity and antigenicity for application in the cardiovascular field. This review summarizes the recent progress and remaining obstacles in targeting mitochondria as a novel therapeutic option for CVD. The advantages of nanoparticle delivery over un-targeted strategies are also discussed.

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 ß-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. The expression levels of Mhrt, Brg1 and Myh6/Myh7 have been assessed in rat models of hyperthyroidism or acute myocardial ischemia/reperfusion (IR) treated with T3 replacement therapy. To gain mechanistic insights, in silico analyses and site-directed mutagenesis have been adopted in combination with gene reporter assays and loss or gain of function strategies in cultured cardiomyocytes. Our results indicate a pivotal role of Mhrt over-expression in the T3-dependent regulation of Myh switch. Mechanistically, T3 activates the Mhrt promoter at two putative thyroid hormone responsive elements (TRE) located in a crucial region that is necessary for both Mhrt activation and Brg1-dependent Mhrt repression. This newly identified T3 mode of action requires DNA chromatinization and is critically involved in mitigating the repressive function of the Brg1 protein on Mhrt promoter. In addition, T3 is also able to prevent the Brg1 over-expression observed in the post-IR setting through a pathway that might entail the T3-mediated up-regulation of miR-208a. Taken together, our data evidence a novel T3-responsive network of cross-talking epigenetic factors that dictates the cardiac Myh composition and could be of great translational relevance.

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. Study observation period was 13 weeks. Inositols were administered as mixture of myo-inositol and d-chiro-inositol in the drinking water. Effects of inositols were evaluated based on electrical, structural, and functional cardiac features, autonomic sympatho-vagal balance and arrhythmogenic susceptibility to adrenergic challenge. Heart samples were collected for histological evaluations and transcriptional analyses of genes involved in defining the shape and propagation of the action potential, fatty acid metabolism and oxidative stress. Inositol supplementation significantly restored control values of heart rate and QTc interval on ECG and of sympatho-vagal balance. Moreover, it blunted the increase in left ventricular mass and cardiomyocyte hypertrophy, reversed diastolic dysfunction, reduced the susceptibility to arrhythmic events and restored the expression level of cardiac genes altered by HFD. The present study shows, for the first time, how a short period of supplementation with inositols is able to ameliorate the HFD-induced electrical, structural and functional heart alterations including ventricular remodeling. Results provide a new insight into the cardioprotective effect of inositols, which could pave the way for a novel therapeutic approach to the treatment of HFD obesity-induced heart dysfunction.

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. ANIMALS/METHODS: In C57BL6 mice fed on a high fat (n = 20, HF-group) or standard diet (n = 20, C-group) for 13 weeks, balanced by sex and age, we examined heart morphology and function by high-frequency ultrasounds and electric activity by surface ECG. Besides, the autonomic sympathovagal balance (heart-rate variability) and the arrhythmogenic susceptibility to adrenergic challenge (i.p. isoproterenol) were compared in the two groups, as well as glucose tolerance (i.p. glucose test) and liver steatosis (ultrasounds). RESULTS: Body weight in HF-group exceeded C-group at the end of the experiment (+28% p < 0.01). An abnormal ventricular repolarization (long QTc on ECG) together with impaired LV filling rate and increased LV mass was found in HF-group as compared to C. Moreover, HF-group showed higher heart rate, unbalanced autonomic control with adrenergic prevalence and a greater susceptibility to develop rhythm disturbances under adrenergic challenge (i.p. isoprenaline). Impaired glucose tolerance and higher liver fat accumulation were also found in HF mice compared to C. CONCLUSIONS: The described murine model of 13 weeks on HF diet, well reproduced the cardiovascular and metabolic disorders reported in clinical obesity, suggesting its potential utility as translational mean suitable for testing new pharmaco-therapeutic approaches to the treatment of obesity and its comorbidity.

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. While Ang1 promotes the activation of survival pathways and the stabilization of the normal mature vessels, Ang2 can either favor vessel destabilization and leakage or promote abnormal EC proliferation in a context-dependent manner. Altered Ang1/Ang2 balance has been reported in various pathological conditions in association with inflammation and deregulated angiogenesis. In particular, increased Ang2 levels have been documented in human cancer and cardiovascular disease (CVD), including ischemic myocardial injury, heart failure and other cardiovascular complications secondary to diabetes, chronic renal damage and hypertension. Despite the obvious phenotypic differences, CVD and cancer share some common Ang2-dependent etiopathological mechanisms such as inflammation, epithelial (or endothelial) to mesenchymal transition, and adverse vascular network remodeling. Interestingly, both cancer and CVD are negatively affected by thyroid hormone dyshomeostasis. This review provides an overview of the complex Ang2-dependent signaling involved in CVD and cancer, as well as a survey of the related clinical literature. Moreover, on the basis of recent molecular acquisitions in an experimental model of post ischemic cardiac disease, the putative novel role of the thyroid hormone in the regulation of Ang1/Ang2 balance is also briefly discussed.

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. Among them, the epigenetic remodeling of chromatin structure and the interplay with non-coding RNA have emerged as novel TH-dependent pathways that add further degrees of complexity and broaden the network of genes controlled by TH signaling. Increasing experimental and clinical findings indicate that aberrant function of these regulatory mechanisms promotes the evolution of cardiac disorders such as post-ischemic injury, pathological hypertrophy, and heart failure, which may be reversed by the correction of the underlying TH dyshomeostasis. To encourage the clinical implementation of a TH replacement strategy in cardiac disease, here we discuss the crucial effect of epigenetic modifications and control of non-coding RNA in TH-dependent regulation of biological processes relevant for cardiac disease evolution.

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, Ca2+ 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. In this context, mitochondrial quality control (MQC) represents an expanding research topic and therapeutic target in the field of cardiac physiology. MQC is a multi-tier surveillance system operating at the protein, organelle, and cell level to repair or eliminate damaged mitochondrial components and replace them by biogenesis. Novel evidence highlights the critical role of thyroid hormones (TH) in regulating multiple aspects of MQC, resulting in increased organelle turnover, improved mitochondrial bioenergetics, and the retention of cell function. In the present review, these emerging protective effects are discussed in the context of cardiac ischemia-reperfusion (IR) and heart failure, focusing on MQC as a strategy to blunt the propagation of connected dangerous signaling cascades and limit adverse remodeling. A better understanding of such TH-dependent signaling could provide insights into the development of mitochondria-targeted treatments in patients with cardiac disease.

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. As evidenced by mRNA and miRNA expression profiling, the T3 supplementation reverted the expression of 87 genes and 11 miRNAs that were dysregulated in the untreated group. In silico crossing and functional analysis of the T3-associated differentially expressed transcripts, identified a signature of interconnected miRNA-gene regulatory circuits that confer resistance to noxious cascades of acute stress. In this network the T3-down-regulated Tp53, Jun and Sp1 transcription factors emerge as critical nodes linking intrinsic cell death and oxidative stress pathways to adverse remodeling cascades. The data presented here provide a novel insight into the molecular basis of T3 cardioprotection in the early post-IR phase and highlight the contribution of a previously unappreciated complex T3-regulatory network that may be helpful in translating T3 replacement into clinical practice.

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.Adopting this model, our study aimed to investigate the effects of T3 on the capillary index and the expression of angiogenic genes as the angiopoietins 1/2 and tyrosine kinase receptor system, in the thoracic aorta and in the left ventricle. In the thoracic aorta, T3 infusion significantly improved the angiogenic sprouting and angiopoietin 2 expression. Instead, Sham-T3 group did not show any significant increment of capillary density and angiopoietin 2 expression. In the area at risk (AAR) of the left ventricle, T3 infusion did not increase capillary density but restored levels of angiopoietin 1, which were reduced in I/R group. Angiopoietin 2 levels were similar to Sham group and unchanged by T3 administration. In the remote zone, T3 induced a significant increment of both angiopoietin 1/2. In conclusion, T3 infusion induced a different response of angiopoietin 1/2 between the ventricle (the AAR and the remote zone) and the thoracic aorta, probably reflecting the different action of angiopoietin 1/2 in cardiomyocytes and endothelial cells. Overall, these data suggest a new aspect of T3-mediated cardioprotection through angiogenesis.

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. Thyroid system is strictly interconnected with heart homeostasis, and recent studies highlighted its role in cardioprotection, in particular through the preservation of mitochondrial function and morphology, the antifibrotic and proangiogenetic effect and also to the potential induction of cell regeneration and growth. The objective of this review was to highlight the cardioprotective role of triiodothyronine in the complexity of post-ischemic disease evolution.

Early and Short-term Triiodothyronine Supplementation Prevents Adverse Postischemic Cardiac Remodeling: Role of Transforming Growth Factor-ß1 and Antifibrotic miRNA Signaling.

Activation of transforming growth factor (TGF)-ß1 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 TGFß1-dependent profibrotic cascade to confer long-lasting cardioprotection against adverse CR. Twenty-four hours after I/R, rats that developed the Low-T3S were randomly assigned to receive a 48-h infusion of 6 µg/kg/d T3 (I/R-L+T3) or saline (I/R-L) and sacrificed at 3 or 14 d post-I/R. Three days post-I/R, Low-T3S correction favored functional cardiac recovery. This effect was paralleled by a drop in TGFß1 and increased miR-133a, miR-30c and miR-29c in the infarcted myocardium. Consistently, connective transforming growth factor (CTGF) and matrix metalloproteinase-2(MMP-2), validated targets of the above miRNAs, were significantly reduced. Fourteen days post-I/R, the I/R-L+T3 rats presented a significant reduction of scar size with a better preservation of cardiac performance and LV chamber geometry. At this time, TGFß1 and miR-29c levels were in the normal range in both groups, whereas miR-30c-133a, MMP-2 and CTGF remained significantly altered in the I/R group. In conclusion, the antifibrotic effect exerted by T3 in the early phase of postischemic wound healing triggers a persistent cardioprotective response that hampers the progression of heart dysfunction and 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. The low T3 group exhibits the most compromised cardiac performance along with the worst mitochondrial activity. Accordingly, our results show a different remodeling of the mitochondrial proteome in the presence or absence of a LT3S, with alterations in groups of proteins that play a key role in energy metabolism, quality control and regulation of cell death pathways. Overall, our findings highlight a relationship between LT3S in the early post IR and poor cardiac and mitochondrial outcomes, and suggest a potential implication of thyroid hormone in the cardio-protection and tissue remodeling in ischemic disease.