Role of Vasoactive Hormone-Induced Signal Transduction in Cardiac Hypertrophy and Heart Failure.

Heart failure is the common concluding pathway for a majority of cardiovascular diseases and is associated with cardiac dysfunction. Since heart failure is invariably preceded by adaptive or maladaptive cardiac hypertrophy, several biochemical mechanisms have been proposed to explain the development of cardiac hypertrophy and progression to heart failure. One of these includes the activation of different neuroendocrine systems for elevating the circulating levels of different vasoactive hormones such as catecholamines, angiotensin II, vasopressin, serotonin and endothelins. All these hormones are released in the circulation and stimulate different signal transduction systems by acting on their respective receptors on the cell membrane to promote protein synthesis in cardiomyocytes and induce cardiac hypertrophy. The elevated levels of these vasoactive hormones induce hemodynamic overload, increase ventricular wall tension, increase protein synthesis and the occurrence of cardiac remodeling. In addition, there occurs an increase in proinflammatory cytokines and collagen synthesis for the induction of myocardial fibrosis and the transition of adaptive to maladaptive hypertrophy. The prolonged exposure of the hypertrophied heart to these vasoactive hormones has been reported to result in the oxidation of catecholamines and serotonin via monoamine oxidase as well as the activation of NADPH oxidase via angiotensin II and endothelins to promote oxidative stress. The development of oxidative stress produces subcellular defects, Ca2+-handling abnormalities, mitochondrial Ca2+-overload and cardiac dysfunction by activating different proteases and depressing cardiac gene expression, in addition to destabilizing the extracellular matrix upon activating some metalloproteinases. These observations support the view that elevated levels of various vasoactive hormones, by producing hemodynamic overload and activating their respective receptor-mediated signal transduction mechanisms, induce cardiac hypertrophy. Furthermore, the occurrence of oxidative stress due to the prolonged exposure of the hypertrophied heart to these hormones plays a critical role in the progression of heart failure.

Levels of Small Extracellular Vesicles Containing hERG-1 and Hsp47 as Potential Biomarkers for Cardiovascular Diseases.

The diagnosis of cardiovascular disease (CVD) is still limited. Therefore, this study demonstrates the presence of human ether-a-go-go-related gene 1 (hERG1) and heat shock protein 47 (Hsp47) on the surface of small extracellular vesicles (sEVs) in human peripheral blood and their association with CVD. In this research, 20 individuals with heart failure and 26 participants subjected to cardiac stress tests were enrolled. The associations between hERG1 and/or Hsp47 in sEVs and CVD were established using Western blot, flow cytometry, electron microscopy, ELISA, and nanoparticle tracking analysis. The results show that hERG1 and Hsp47 were present in sEV membranes, extravesicularly exposing the sequences 430AFLLKETEEGPPATE445 for hERG1 and 169ALQSINEWAAQTT- DGKLPEVTKDVERTD196 for Hsp47. In addition, upon exposure to hypoxia, rat primary cardiomyocytes released sEVs into the media, and human cardiomyocytes in culture also released sEVs containing hERG1 (EV-hERG1) and/or Hsp47 (EV-Hsp47). Moreover, the levels of sEVs increased in the blood when cardiac ischemia was induced during the stress test, as well as the concentrations of EV-hERG1 and EV-Hsp47. Additionally, the plasma levels of EV-hERG1 and EV-Hsp47 decreased in patients with decompensated heart failure (DHF). Our data provide the first evidence that hERG1 and Hsp47 are present in the membranes of sEVs derived from the human cardiomyocyte cell line, and also in those isolated from human peripheral blood. Total sEVs, EV-hERG1, and EV-Hsp47 may be explored as biomarkers for heart diseases such as heart failure and cardiac ischemia.

DEAD-box helicase 17 (DDX17) protects cardiac function by promoting mitochondrial homeostasis in heart failure.

DEAD-box helicase 17 (DDX17) is a typical member of the DEAD-box family with transcriptional cofactor activity. Although DDX17 is abundantly expressed in the myocardium, its role in heart is not fully understood. We generated cardiomyocyte-specific Ddx17-knockout mice (Ddx17-cKO), cardiomyocyte-specific Ddx17 transgenic mice (Ddx17-Tg), and various models of cardiomyocyte injury and heart failure (HF). DDX17 is downregulated in the myocardium of mouse models of heart failure and cardiomyocyte injury. Cardiomyocyte-specific knockout of Ddx17 promotes autophagic flux blockage and cardiomyocyte apoptosis, leading to progressive cardiac dysfunction, maladaptive remodeling and progression to heart failure. Restoration of DDX17 expression in cardiomyocytes protects cardiac function under pathological conditions. Further studies showed that DDX17 can bind to the transcriptional repressor B-cell lymphoma 6 (BCL6) and inhibit the expression of dynamin-related protein 1 (DRP1). When DDX17 expression is reduced, transcriptional repression of BCL6 is attenuated, leading to increased DRP1 expression and mitochondrial fission, which in turn leads to impaired mitochondrial homeostasis and heart failure. We also investigated the correlation of DDX17 expression with cardiac function and DRP1 expression in myocardial biopsy samples from patients with heart failure. These findings suggest that DDX17 protects cardiac function by promoting mitochondrial homeostasis through the BCL6-DRP1 pathway in heart failure.

A novel histone deacetylase inhibitor Se-SAHA attenuates isoproterenol-induced heart failure via antioxidative stress and autophagy inhibition.

Heart failure is associated with histone deacetylase (HDAC) regulation of gene expression, the inhibition of which is thought to be beneficial for heart failure therapy. Here, we explored the cardioprotective effects and underlying mechanism of a novel selenium-containing HDAC inhibitor, Se-SAHA, on isoproterenol (ISO)-induced heart failure. We found that pretreatment with Se-SAHA attenuated ISO-induced cardiac hypertrophy and fibrosis in neonatal rat ventricular myocytes (NRVMs). Se-SAHA significantly attenuated the generation of ISO-induced reactive oxygen species (ROS) and restored the expression levels of superoxide dismutase 2 (SOD2) and heme oxygenase-1 (HO-1) in vitro. Furthermore, Se-SAHA pretreatment prevented the accumulation of autophagosomes. Se-SAHA reversed the high expression of HDAC1 and HDAC6 induced by ISO incubation. However, after the addition of the HDAC agonist, the effect of Se-SAHA on blocking autophagy was inhibited. Using ISO-induced mouse models, cardiac ventricular contractile dysfunction, hypertrophy, and fibrosis was reduced treated by Se-SAHA. In addition, Se-SAHA inhibited HDAC1 and HDAC6 overexpression in ISO-treated mice. Se-SAHA treatment significantly increased the activity of SOD2 and improved the ability to eliminate free radicals. Se-SAHA hindered the excessive levels of the microtubule-associated protein 1 light chain 3 (LC3)-II and Beclin-1 in heart failure mice. Collectively, our results indicate that Se-SAHA exerts cardio-protection against ISO-induced heart failure via antioxidative stress and autophagy inhibition.

Porcine Model of Hypertrophy-Independent Left Ventricular Stiffening via Repetitive Pressure Overload.

Diastolic dysfunction arising from alterations in myocardial structure and/or function is a central component of several cardiovascular disorders, including heart failure with preserved ejection fraction (HFpEF). Basic research aimed at understanding underlying mechanisms contributing to the development of diastolic dysfunction has generally centered upon models of left ventricular (LV) hypertrophy arising from persistent and severe elevations in myocardial afterload (e.g., aortic banding). Mechanisms of hypertrophy-independent diastolic dysfunction, on the other hand, have received less attention, even though overt anatomic LV hypertrophy is absent in many HFpEF patients. Here, we describe the development of a novel porcine model of repetitive pressure overload (RPO) in which chronic, intermittent exposure to transient episodes of hypertension produces an increase in LV stiffness, interstitial fibrosis, cardiomyocyte hypertrophy, and capillary rarefaction without significant changes in LV mass. This model offers important insight into how diastolic dysfunction and HFpEF may develop in the absence of comorbidities, sustained hypertension, or LV hypertrophy, while also providing a useful translational research tool for investigation of novel therapeutic approaches to restore myocardial compliance and improve diastolic function.

The Sugen/Hypoxia Rat Model for Pulmonary Hypertension and Right Heart Failure.

Pulmonary hypertension (PH) is a devastating disease, characterized by complex remodeling of the pulmonary vasculature. PH is classified into five groups based on different etiology, pathology, as well as therapy and prognosis. Animal models are essential for the study of underlying mechanisms, pathophysiology, and preclinical testing of new therapies for PH. The complexity of the disease with different clinical entities dictates the necessity for more than one animal model to resemble PH, as a single model cannot imitate the broad spectrum of human PH.Here we describe a detailed protocol for creating a rat model of PH with right ventricular (RV) failure. Furthermore, we present how to characterize it hemodynamically by invasive measurements of RV and pulmonary arterial (PA) pressures. Animals subjected to this model display severe pulmonary vascular remodeling and RV dysfunction. In this model, rats undergo a single subcutaneous injection of Sugen (SU5416, a vascular endothelial growth factor inhibitor) and are immediately exposed to chronic hypoxia in a hypoxia chamber for 3-6 weeks. This Sugen/Hypoxia rat model resembles Group 1 PH.

Heart failure potentially affects the cortical structure of the brain.

BACKGROUND: Heart failure (HF) has been reported to affect cerebral cortex structure, but the underlying cause has not been determined. This study used Mendelian randomization (MR) to reveal the causal relationship between HF and structural changes in the cerebral cortex. METHODS: HF was defined as the exposure variable, and cerebral cortex structure was defined as the outcome variable. Inverse-variance weighted (IVW), MR-Egger regression and weighted median (WME) were performed for MR analysis; MR-PRESSO and Egger's intercept was used to test horizontal pleiotropy; and "leave-one-out" was used for sensitivity analysis. RESULTS: Fifty-two single nucleotide polymorphisms (SNPs) were defined as instrumental variables (IVs), and there was no horizontal pleiotropy in the IVs. According to the IVW analysis, the OR and 95% CI of cerebral cortex thickness were 0.9932 (0.9868-1.00) (P=0.0402), and the MR-Egger intercept was -15.6× 10-5 (P = 0.7974) and the Global test pval was 0.078. The P-value of the cerebral cortex surface was 0.2205, and the MR-Egger intercept was -34.69052 (P= 0.6984) and the Global Test pval was 0.045. HF had a causal effect on the surface area of the caudal middle frontal lobule (P=0.009), insula lobule (P=0.01), precuneus lobule (P=0.049) and superior parietal lobule (P=0.044). CONCLUSIONS: HF was potentially associated with changes in cortical thickness and in the surface area of the caudal middle frontal lobule, insula lobule, precuneus lobule and superior parietal lobule.

Mapping the interplay of immunoproteasome and autophagy in different heart failure phenotypes.

Proper protein degradation is required for cellular protein homeostasis and organ function. Particularly, in post-mitotic cells, such as cardiomyocytes, unbalanced proteolysis due to inflammatory stimuli and oxidative stress contributes to organ dysfunction. To ensure appropriate protein turnover, eukaryotic cells exert two main degradation systems, the ubiquitin-proteasome-system and the autophagy-lysosome-pathway. It has been shown that proteasome activity affects the development of cardiac dysfunction differently, depending on the type of heart failure. Studies analyzing the inducible subtype of the proteasome, the immunoproteasome (i20S), demonstrated that the i20S plays a double role in diseased hearts. While i20S subunits are increased in cardiac hypertrophy, atrial fibrillation and partly in myocarditis, the opposite applies to diabetic cardiomyopathy and ischemia/reperfusion injury. In addition, the i20S appears to play a role in autophagy modulation depending on heart failure phenotype. This review summarizes the current literature on the i20S in different heart failure phenotypes, emphasizing the two faces of i20S in injured hearts. A selection of established i20S inhibitors is introduced and signaling pathways linking the i20S to autophagy are highlighted. Mapping the interplay of the i20S and autophagy in different types of heart failure offers potential approaches for developing treatment strategies against heart failure.

PBX/Knotted 1 homeobox-2 (PKNOX2) is a novel regulator of myocardial fibrosis.

Much effort has been made to uncover the cellular heterogeneities of human hearts by single-nucleus RNA sequencing. However, the cardiac transcriptional regulation networks have not been systematically described because of the limitations in detecting transcription factors. In this study, we optimized a pipeline for isolating nuclei and conducting single-nucleus RNA sequencing targeted to detect a higher number of cell signal genes and an optimal number of transcription factors. With this unbiased protocol, we characterized the cellular composition of healthy human hearts and investigated the transcriptional regulation networks involved in determining the cellular identities and functions of the main cardiac cell subtypes. Particularly in fibroblasts, a novel regulator, PKNOX2, was identified as being associated with physiological fibroblast activation in healthy hearts. To validate the roles of these transcription factors in maintaining homeostasis, we used single-nucleus RNA-sequencing analysis of transplanted failing hearts focusing on fibroblast remodelling. The trajectory analysis suggested that PKNOX2 was abnormally decreased from fibroblast activation to pathological myofibroblast formation. Both gain- and loss-of-function in vitro experiments demonstrated the inhibitory role of PKNOX2 in pathological fibrosis remodelling. Moreover, fibroblast-specific overexpression and knockout of PKNOX2 in a heart failure mouse model induced by transverse aortic constriction surgery significantly improved and aggravated myocardial fibrosis, respectively. In summary, this study established a high-quality pipeline for single-nucleus RNA-sequencing analysis of heart muscle. With this optimized protocol, we described the transcriptional regulation networks of the main cardiac cell subtypes and identified PKNOX2 as a novel regulator in suppressing fibrosis and a potential therapeutic target for future translational studies.

Single-cell transcriptomics in MI identify Slc25a4 as a new modulator of mitochondrial malfunction and apoptosis-associated cardiomyocyte subcluster.

Myocardial infarction (MI) is the leading cause of premature death. The death of cardiomyocytes (CMs) and the dysfunction of the remaining viable CMs are the main pathological factors contributing to heart failure (HF) following MI. This study aims to determine the transcriptional profile of CMs and investigate the heterogeneity among CMs under hypoxic conditions. Single-cell atlases of the heart in both the sham and MI groups were developed using single-cell data (GSE214611) downloaded from Gene Expression Omnibus (GEO) database ( https://www.ncbi.nlm.nih.gov/geo/ ). The heterogeneity among CMs was explored through various analyses including enrichment, pseudo time, and intercellular communication analysis. The marker gene of C5 was identified using differential expression analysis (DEA). Real-time polymerase chain reaction (RT-PCR), bulk RNA-sequencing dataset analysis, western blotting, immunohistochemical and immunofluorescence staining, Mito-Tracker staining, TUNEL staining, and flow cytometry analysis were conducted to validate the impact of the marker gene on mitochondrial function and cell apoptosis of CMs under hypoxic conditions. We identified a cell subcluster named C5 that exhibited a close association with mitochondrial malfunction and cellular apoptosis characteristics, and identified Slc25a4 as a significant biomarker of C5. Furthermore, our findings indicated that the expression of Slc25a4 was increased in failing hearts, and the downregulation of Slc25a4 improved mitochondrial function and reduced cell apoptosis. Our study significantly identified a distinct subcluster of CMs that exhibited strong associations with ventricular remodeling following MI. Slc25a4 served as the hub gene for C5, highlighting its significant potential as a novel therapeutic target for MI.

Cardiomyocyte-specific deletion of the mitochondrial transporter Abcb10 causes cardiac dysfunction via lysosomal-mediated ferroptosis.

Heart function is highly dependent on mitochondria, which not only produce energy but also regulate many cellular functions. Therefore, mitochondria are important therapeutic targets in heart failure. Abcb10 is a member of the ABC transporter superfamily located in the inner mitochondrial membrane and plays an important role in haemoglobin synthesis, biliverdin transport, antioxidant stress, and stabilization of the iron transporter mitoferrin-1. However, the mechanisms underlying the impairment of mitochondrial transporters in the heart remain poorly understood. Here, we generated mice with cardiomyocyte-specific loss of Abcb10. The Abcb10 knockouts exhibited progressive worsening of cardiac fibrosis, increased cardiovascular risk markers and mitochondrial structural abnormalities, suggesting that the pathology of heart failure is related to mitochondrial dysfunction. As the mitochondrial dysfunction was observed early but mildly, other factors were considered. We then observed increased Hif1α expression, decreased NAD synthase expression, and reduced NAD+ levels, leading to lysosomal dysfunction. Analysis of ABCB10 knockdown HeLa cells revealed accumulation of Fe2+ and lipid peroxides in lysosomes, leading to ferroptosis. Lipid peroxidation was suppressed by treatment with iron chelators, suggesting that lysosomal iron accumulation is involved in ferroptosis. We also observed that Abcb10 knockout cardiomyocytes exhibited increased ROS production, iron accumulation, and lysosomal hypertrophy. Our findings suggest that Abcb10 is required for the maintenance of cardiac function and reveal a novel pathophysiology of chronic heart failure related to lysosomal function and ferroptosis.

Angiotension II directly bind P2X7 receptor to induce myocardial ferroptosis and remodeling by activating human antigen R.

Continuous remodeling of the heart can result in adverse events such as reduced myocardial function and heart failure. Available evidence indicates that ferroptosis is a key process in the emergence of cardiac disease. P2 family purinergic receptor P2X7 receptor (P2X7R) activation plays a crucial role in numerous aspects of cardiovascular disease. The aim of this study was to elucidate any potential interactions between P2X7R and ferroptosis in cardiac remodeling stimulated by angiotensin II (Ang II), and P2X7R knockout mice were utilized to explore the role of P2X7R and elucidate its underlying mechanism through molecular biological methods. Ferroptosis is involved in cardiac remodeling, and P2X7R deficiency significantly alleviates cardiac dysfunction, remodeling, and ferroptosis induced by Ang II. Mechanistically, Ang II interacts with P2X7R directly, and LYS-66 and MET-212 in the in the ATP binding pocket form a binding complex with Ang II. P2X7R blockade influences HuR-targeted GPX4 and HO-1 mRNA stability by affecting the shuttling of HuR from the nucleus to the cytoplasm and its expression. These results suggest that focusing on P2X7R could be a possible therapeutic approach for the management of hypertensive heart failure.

Targeting cardiomyocyte cell cycle regulation in heart failure.

Heart failure continues to be a significant global health concern, causing substantial morbidity and mortality. The limited ability of the adult heart to regenerate has posed challenges in finding effective treatments for cardiac pathologies. While various medications and surgical interventions have been used to improve cardiac function, they are not able to address the extensive loss of functioning cardiomyocytes that occurs during cardiac injury. As a result, there is growing interest in understanding how the cell cycle is regulated and exploring the potential for stimulating cardiomyocyte proliferation as a means of promoting heart regeneration. This review aims to provide an overview of current knowledge on cell cycle regulation and mechanisms underlying cardiomyocyte proliferation in cases of heart failure, while also highlighting established and novel therapeutic strategies targeting this area for treatment purposes.

AICAR confers prophylactic cardioprotection in doxorubicin-induced heart failure in rats.

Doxorubicin (DOX) is a widely used chemotherapeutic agent that can cause serious cardiotoxic side effects, leading to heart failure (HF). Impaired mitochondrial function is thought to be key factor driving progression into HF. We have previously shown in a rat model of DOX-HF that heart failure with reduced ejection fraction correlates with mitochondrial loss and dysfunction. Adenosine monophosphate-dependent kinase (AMPK) is a cellular energy sensor, regulating mitochondrial biogenesis and energy metabolism, including fatty acid oxidation. We hypothesised that AMPK activation could restore mitochondrial function and therefore be a novel cardioprotective strategy for the prevention of DOX-HF. Consequently, we set out to assess whether 5-aminoimidazole-4-carboxamide 1-ß-D-ribofuranoside (AICAR), an activator of AMPK, could prevent cardiac functional decline in this chronic intravenous rat model of DOX-HF. In line with our hypothesis, AICAR improved cardiac systolic function. AICAR furthermore improved cardiac mitochondrial fatty acid oxidation, independent of mitochondrial number, and in the absence of observable AMPK-activation. In addition, we found that AICAR prevented loss of myocardial mass. RNAseq analysis showed that this may be driven by normalisation of pathways associated with ribosome function and protein synthesis, which are impaired in DOX-treated rat hearts. AICAR furthermore prevented dyslipidemia and excessive body-weight loss in DOX-treated rats, which may contribute to preservation of myocardial mass. Though it is unclear whether AICAR exerted its cardioprotective effect through cardiac or extra-cardiac AMPK-activation or via an AMPK-independent effect, these results show promise for the use of AICAR as a cardioprotective agent in DOX-HF to both preserve cardiac function and mass.

Overexpressing of the GIPC1 protects against pathological cardiac remodelling.

OBJECTIVE: Pathological cardiac remodelling, including cardiac hypertrophy and fibrosis, is a key pathological process in the development of heart failure. However, effective therapeutic approaches are limited. The ß-adrenergic receptors are pivotal signalling molecules in regulating cardiac function. G-alpha interacting protein (GAIP)-interacting protein, C-terminus 1 (GIPC1) is a multifunctional scaffold protein that directly binds to the C-terminus of ß1-adrenergic receptor (ß1-adrenergic receptor). However, little is known about its roles in heart function. Therefore, we investigated the role of GIPC1 in cardiac remodelling and its underlying molecular mechanisms. METHODS: Pathological cardiac remodelling in mice was established via intraperitoneal injection of isoprenaline for 14 d or transverse aortic constriction surgery for 8 weeks. Myh6-driving cardiomyocyte-specific GIPC1 conditional knockout (GIPC1 cKO) mice and adeno-associated virus 9 (AAV9)-mediated GIPC1 overexpression mice were used. The effect of GIPC1 on cardiac remodelling was assessed using echocardiographic, histological, and biochemical analyses. RESULTS: GIPC1 expression was consistently reduced in the cardiac remodelling model. GIPC1 cKO mice exhibited spontaneous abnormalities, including cardiac hypertrophy, fibrosis, and systolic dysfunction. In contrast, AAV9-mediated GIPC1 overexpression in the heart attenuated isoproterenol-induced pathological cardiac remodelling in mice. Mechanistically, GIPC1 interacted with the ß1-adrenergic receptor and stabilised its expression by preventing its ubiquitination and degradation, maintaining the balance of ß1-adrenergic receptor/ß2-adrenergic receptor, and inhibiting hyperactivation of the mitogen-activated protein kinase signalling pathway. CONCLUSIONS: These results suggested that GIPC1 plays a cardioprotective role and is a promising therapeutic target for the treatment of cardiac remodelling and heart failure.

Cellular and molecular mechanisms driving cardiac tissue fibrosis: On the precipice of personalized and precision medicine.

Cardiac fibrosis is a significant contributor to heart failure, a condition that continues to affect a growing number of patients worldwide. Various cardiovascular comorbidities can exacerbate cardiac fibrosis. While fibroblasts are believed to be the primary cell type underlying fibrosis, recent and emerging data suggest that other cell types can also potentiate or expedite fibrotic processes. Over the past few decades, clinicians have developed therapeutics that can blunt the development and progression of cardiac fibrosis. While these strategies have yielded positive results, overall clinical outcomes for patients suffering from heart failure continue to be dire. Herein, we overview the molecular and cellular mechanisms underlying cardiac tissue fibrosis. To do so, we establish the known mechanisms that drive fibrosis in the heart, outline the diagnostic tools available, and summarize the treatment options used in contemporary clinical practice. Finally, we underscore the critical role the immune microenvironment plays in the pathogenesis of cardiac fibrosis.

PRDX6 alleviated heart failure by inhibiting doxorubicin-induced ferroptosis through the JAK2/STAT1 pathway inactivation.

Peroxiredoxin 6 (PRDX6) is a protective biomarker associated with ferroptosis in heart failure (HF). This study investigated the specific mechanism of PRDX6 on doxorubicin (DOX)-induced ferroptosis in HF. Wistar rats and H9c2 cells were induced by DOX to construct HF models. Pathological changes and collagen deposition in myocardium were investigated using HE and Masson staining. PRDX6 levels, indexes of ferroptosis, and JAK2/STAT1 pathway were detected by qRT-PCR, Western blot, and biochemical kits. DOX promoted heart weight/body weight, increased inflammation and collagen deposition, increased PTGS2 and MDA levels, and decreased SLC7A11, GPX4, FTH1, and PRDX6 levels in myocardium. PRDX6 overexpression reduced PTGS2, MDA, Fe2+, and LDH levels, inhibited JAK2 and STAT1 phosphorylation, and increased SLC7A11, GPX4, and FTH1 levels in DOX-added H9c2 cells. RO8191 and erastin reversed the inhibition of PRDX6 on ferroptosis through the JAK2/STAT1 pathway. Overall, PRDX6 alleviated HF by inhibiting DOX-induced ferroptosis through the JAK2/STAT1 pathway inactivation.

Small Extracellular Vesicles From Infarcted and Failing Heart Accelerate Tumor Growth.

BACKGROUND: Myocardial infarction (MI) and heart failure are associated with an increased incidence of cancer. However, the mechanism is complex and unclear. Here, we aimed to test our hypothesis that cardiac small extracellular vesicles (sEVs), particularly cardiac mesenchymal stromal cell-derived sEVs (cMSC-sEVs), contribute to the link between post-MI left ventricular dysfunction (LVD) and cancer. METHODS: We purified and characterized sEVs from post-MI hearts and cultured cMSCs. Then, we analyzed cMSC-EV cargo and proneoplastic effects on several lines of cancer cells, macrophages, and endothelial cells. Next, we modeled heterotopic and orthotopic lung and breast cancer tumors in mice with post-MI LVD. We transferred cMSC-sEVs to assess sEV biodistribution and its effect on tumor growth. Finally, we tested the effects of sEV depletion and spironolactone treatment on cMSC-EV release and tumor growth. RESULTS: Post-MI hearts, particularly cMSCs, produced more sEVs with proneoplastic cargo than nonfailing hearts did. Proteomic analysis revealed unique protein profiles and higher quantities of tumor-promoting cytokines, proteins, and microRNAs in cMSC-sEVs from post-MI hearts. The proneoplastic effects of cMSC-sEVs varied with different types of cancer, with lung and colon cancers being more affected than melanoma and breast cancer cell lines. Post-MI cMSC-sEVs also activated resting macrophages into proangiogenic and protumorigenic states in vitro. At 28-day follow-up, mice with post-MI LVD developed larger heterotopic and orthotopic lung tumors than did sham-MI mice. Adoptive transfer of cMSC-sEVs from post-MI hearts accelerated the growth of heterotopic and orthotopic lung tumors, and biodistribution analysis revealed accumulating cMSC-sEVs in tumor cells along with accelerated tumor cell proliferation. sEV depletion reduced the tumor-promoting effects of MI, and adoptive transfer of cMSC-sEVs from post-MI hearts partially restored these effects. Finally, spironolactone treatment reduced the number of cMSC-sEVs and suppressed tumor growth during post-MI LVD. CONCLUSIONS: Cardiac sEVs, specifically cMSC-sEVs from post-MI hearts, carry multiple protumorigenic factors. Uptake of cMSC-sEVs by cancer cells accelerates tumor growth. Treatment with spironolactone significantly reduces accelerated tumor growth after MI. Our results provide new insight into the mechanism connecting post-MI LVD to cancer and propose a translational option to mitigate this deadly association.