Resident cardiac macrophages mediate adaptive myocardial remodeling.

Cardiac macrophages represent a heterogeneous cell population with distinct origins, dynamics, and functions. Recent studies have revealed that C-C Chemokine Receptor 2 positive (CCR2+) macrophages derived from infiltrating monocytes regulate myocardial inflammation and heart failure pathogenesis. Comparatively little is known about the functions of tissue resident (CCR2-) macrophages. Herein, we identified an essential role for CCR2- macrophages in the chronically failing heart. Depletion of CCR2- macrophages in mice with dilated cardiomyopathy accelerated mortality and impaired ventricular remodeling and coronary angiogenesis, adaptive changes necessary to maintain cardiac output in the setting of reduced cardiac contractility. Mechanistically, CCR2- macrophages interacted with neighboring cardiomyocytes via focal adhesion complexes and were activated in response to mechanical stretch through a transient receptor potential vanilloid 4 (TRPV4)-dependent pathway that controlled growth factor expression. These findings establish a role for tissue-resident macrophages in adaptive cardiac remodeling and implicate mechanical sensing in cardiac macrophage activation.

Metformin induction of heat shock factor 1 activation and the mitochondrial unfolded protein response alleviate cardiac remodeling in spontaneously hypertensive rats.

Heart failure and cardiac remodeling are both characterized by mitochondrial dysfunction. Healthy mitochondria are required for adequate contractile activity and appropriate regulation of cell survival. In the mammalian heart, enhancement of the mitochondrial unfolded protein response (UPRmt) is cardioprotective under pressure overload conditions. We explored the UPRmt and the underlying regulatory mechanism in terms of hypertension-induced cardiac remodeling and the cardioprotective effect of metformin. Male spontaneously hypertensive rats and angiotensin II-treated neonatal rat cardiomyocytes were used to induce cardiac hypertrophy. The results showed that hypertension induced the formation of aberrant mitochondria, characterized by a reduced mtDNA/nDNA ratio and swelling, as well as lower levels of mitochondrial complexes I to V and inhibition of the expression of one protein subunit of each of complexes I to IV. Such changes eventually enlarged cardiomyocytes and increased cardiac fibrosis. Metformin treatment increased the mtDNA/nDNA ratio and regulated the UPRmt, as indicated by increased expression of activating transcription factor 5, Lon protease 1, and heat shock protein 60, and decreased expression of C/EBP homologous protein. Thus, metformin improved mitochondrial ultrastructure and function in spontaneously hypertensive rats. In vitro analyses revealed that metformin reduced the high levels of angiotensin II-induced mitochondrial reactive oxygen species in such animals and stimulated nuclear translocation of heat shock factor 1 (HSF1). Moreover, HSF1 small-interfering RNA reduced the metformin-mediated improvements in mitochondrial morphology and the UPRmt by suppressing hypertrophic signals and cardiomyocyte apoptosis. These results suggest that HSF1/UPRmt signaling contributes to the beneficial effects of metformin. Metformin-mediated targeting of mitochondrial protein homeostasis and modulation of HSF1 levels have potential therapeutic implications in terms of cardiac remodeling.

Kielin/chordin-like protein deficiency aggravates pressure overload-induced cardiac dysfunction and remodeling via P53/P21/CCNB1 signaling in mice.

Targeting cardiac remodeling is regarded as a key therapeutic strategy for heart failure. Kielin/chordin-like protein (KCP) is a secretory protein with 18 cysteine-rich domains and associated with kidney and liver fibrosis. However, the relationship between KCP and cardiac remodeling remains unclear. Here, we aimed to investigate the role of KCP in cardiac remodeling induced by pressure overload and explore its potential mechanisms. Left ventricular (LV) KCP expression was measured with real-time quantitative PCR, western blotting, and immunofluorescence staining in pressure overload-induced cardiac remodeling in mice. Cardiac function and remodeling were evaluated in wide-type (WT) mice and KCP knockout (KO) mice by echocardiography, which were further confirmed by histological analysis with hematoxylin and eosin and Masson staining. RNA sequence was performed with LV tissue from WT and KO mice to identify differentially expressed genes and related signaling pathways. Primary cardiac fibroblasts (CFs) were used to validate the regulatory role and potential mechanisms of KCP during fibrosis. KCP was down-regulated in the progression of cardiac remodeling induced by pressure overload, and was mainly expressed in fibroblasts. KCP deficiency significantly aggravated pressure overload-induced cardiac dysfunction and remodeling. RNA sequence revealed that the role of KCP deficiency in cardiac remodeling was associated with cell division, cell cycle, and P53 signaling pathway, while cyclin B1 (CCNB1) was the most significantly up-regulated gene. Further investigation in vivo and in vitro suggested that KCP deficiency promoted the proliferation of CFs via P53/P21/CCNB1 pathway. Taken together, these results suggested that KCP deficiency aggravates cardiac dysfunction and remodeling induced by pressure overload via P53/P21/CCNB1 signaling in mice.

Mechanism of pro-MMP9 activation in co-culture of pro-inflammatory macrophages and cardiomyocytes.

OBJECTIVE: A wide range of cardiac diseases is associated with inflammation. "Inflamed" heart tissue is infiltrated with pro-inflammatory macrophages which extensively secrete matrix metalloproteinase 9 (MMP9), a regulator of extracellular matrix turnover. As MMP9 is released from macrophages in a latent form, it requires activation. The present study addresses the role of cardiomyocytes in the course of this activation process. METHODS AND RESULTS: In mono- and co-cultures of pro-inflammatory rat macrophages (bone marrow-derived and peritoneal) and cardiomyocytes (H9C2 cell line) gelatin zymography demonstrated that activated macrophages robustly secreted latent pro-MMP9, whereas cardiomyocytes could not produce the enzyme. Co-culturing of the two cell species was critical for pro-MMP9 activation and was also accompanied by processing of cardiomyocyte-secreted pro-MMP2. A cascade of pro-MMP9 activation was initiated on macrophage membrane with pro-MMP2 cleavage. Namely, pro-inflammatory macrophages expressed an active membrane type 1 MMP (MT1MMP), which activated pro-MMP2, which in turn converted pro-MMP9. Downregulation of MT1MMP in macrophages by siRNA abolished activation of both pro-MMP2 and pro-MMP9 in co-culture. In addition, both cell species secreted MMP13 as a further pro-MMP9 activator. In co-culture, activation of pro-MMP13 occurred on membranes of macrophages and was enhanced in presence of active MMP2. Using incubations with recombinant MMPs and isolated macrophage membranes, we demonstrated that while both MMP2 and MMP13 individually had the ability to activate pro-MMP9, their combined action provided a synergistic effect. CONCLUSION: Activation of pro-MMP9 in a co-culture of pro-inflammatory macrophages and cardiomyocytes was the result of a complex interaction of several MMPs on the cell membrane and in the extracellular space. Both cell types contributed critically to pro-MMP9 processing.

CITED4 gene therapy protects against maladaptive cardiac remodeling after ischemia/reperfusion injury in mice.

Cardiac signaling pathways functionally important in the heart's response to exercise often protect the heart against pathological stress, potentially providing novel therapeutic targets. However, it is important to determine which of these pathways can be feasibly targeted in vivo. Transgenic overexpression of exercise-induced CITED4 has been shown to protect against adverse remodeling after ischemia/reperfusion injury (IRI). Here we investigated whether somatic gene transfer of CITED4 in a clinically relevant time frame could promote recovery after IRI. Cardiac CITED4 gene delivery via intravenous AAV9 injections in wild type mice led to an approximately 3-fold increase in cardiac CITED4 expression. After 4 weeks, CITED4-treated animals developed physiological cardiac hypertrophy without adverse remodeling. In IRI, delivery of AAV9-CITED4 after reperfusion resulted in a 6-fold increase in CITED4 expression 1 week after surgery, as well as decreased apoptosis, fibrosis, and inflammatory markers, culminating in a smaller scar and improved cardiac function 8 weeks after IRI, compared with control mice receiving AAV9-GFP. Somatic gene transfer of CITED4 induced a phenotype suggestive of physiological cardiac growth and mitigated adverse remodeling after ischemic injury. These studies support the feasibility of CITED4 gene therapy delivered in a clinically relevant time frame to mitigate adverse ventricular remodeling after ischemic injury.

Inhibition of adenylyl cyclase 8 prevents the upregulation of Orai1 channel, which improves cardiac function after myocardial infarction.

The upregulation of Orai1 and subsequent store-operated Ca2+ entry (SOCE) has been associated with adverse cardiac remodeling and heart failure (HF). However, the mechanism underlying Orai1 upregulation and its role in myocardial infarction remains unclear. Our study investigated the role of Orai1 in activating adenylyl cyclase 8 (AC8) and cyclic AMP (cAMP) response element-binding protein (CREB), as well as its contribution to cardiac dysfunction induced by ischemia and reperfusion (I/R). We found that I/R evoked an increase in the expression of Orai1 and AC8 in rats' hearts, resulting in a substantial rise in diastolic Ca2+ concentration ([Ca2+]i), and reduced ventricular contractions. The expression of Orai1 and AC8 was also increased in ventricular biopsies of post-ischemic HF patients. Mechanistically, we demonstrate that I/R activation of Orai1 stimulated AC8, which produced cAMP and phosphorylated CREB. Subsequently, p-CREB activated the ORAI1 promoter, resulting in Orai1 upregulation and SOCE exacerbation. Intramyocardial administration of AAV9 carrying AC8 short hairpin RNA decreased the expression of AC8, Orai1 and CREB, which restored diastolic [Ca2+]i and improved cardiac contraction. Therefore, our data suggests that the axis composed by Orai1/AC8/CREB plays a critical role in I/R-induced cardiac dysfunction, representing a potential new therapeutic target to limit the progression of the disease toward HF.

Targeting heat shock protein 47 alleviated doxorubicin-induced cardiotoxicity and remodeling in mice through suppression of the NLRP3 inflammasome.

AIM: Doxorubicin-induced cardiotoxicity (DIC) is an increasing problem, occurring in many cancer patients receiving anthracycline chemotherapy, ultimately leading to heart failure (HF). Unfortunately, DIC remains difficult to manage due to an ignorance regarding pathophysiological mechanisms. Our work aimed to evaluate the role of HSP47 in doxorubicin-induced HF, and to explore the molecular mechanisms. METHODS AND RESULTS: Mice were exposed to multi-intraperitoneal injection of doxorubicin (DOX, 4mg/kg/week, for 6 weeks continuously) to produce DIC. HSP47 expression was significantly upregulated in serum and in heart tissue in DOX-treated mice and in isolated cardiomyocytes. Mice with cardiac-specific HSP47 overexpression and knockdown were generated using recombinant adeno-associated virus (rAVV9) injection. Importantly, cardiac-specific HSP47 overexpression exacerbated cardiac dysfunction in DIC, while HSP47 knockdown prevented DOX-induced cardiac dysfunction, cardiac atrophy and fibrosis in vivo and in vitro. Mechanistically, we identified that HSP47 directly interacted with IRE1α in cardiomyocytes. Furthermore, we provided powerful evidence that HSP47-IRE1α complex promoted TXNIP/NLRP3 inflammasome and reinforced USP1-mediated NLRP3 ubiquitination. Moreover, NLRP3 deficiency in vivo conspicuously abolished HSP47-mediated cardiac atrophy and fibrogenesis under DOX condition. CONCLUSION: HSP47 was highly expressed in serum and cardiac tissue after doxorubicin administration. HSP47 contributed to long-term anthracycline chemotherapy-associated cardiac dysfunction in an NLRP3-dependent manner. HSP47 therefore represents a plausible target for future therapy of doxorubicin-induced HF.

Glutamine metabolism improves left ventricular function but not macrophage-mediated inflammation following myocardial infarction.

Glutamine is a critical amino acid that serves as an energy source, building block, and signaling molecule for the heart tissue and the immune system. However, the role of glutamine metabolism in regulating cardiac remodeling following myocardial infarction (MI) is unknown. In this study, we show in adult male mice that glutamine metabolism is altered both in the remote (contractile) area and in infiltrating macrophages in the infarct area after permanent left anterior descending artery occlusion. We found that metabolites related to glutamine metabolism were differentially altered in macrophages at days 1, 3, and 7 after MI using untargeted metabolomics. Glutamine metabolism in live cells was increased after MI relative to no MI controls. Gene expression in the remote area of the heart indicated a loss of glutamine metabolism. Glutamine administration improved left ventricle (LV) function at days 1, 3, and 7 after MI, which was associated with improved contractile and metabolic gene expression. Conversely, administration of BPTES, a pharmacological inhibitor of glutaminase-1, worsened LV function after MI. Neither glutamine nor BPTES administration impacted gene expression or bioenergetics of macrophages isolated from the infarct area. Our results indicate that glutamine metabolism plays a critical role in maintaining LV contractile function following MI and that glutamine administration improves LV function. Glutamine metabolism may also play a role in regulating macrophage function, but macrophages are not responsive to exogenous pharmacological manipulation of glutamine metabolism.NEW & NOTEWORTHY Glutamine metabolism is altered in both infarct macrophages and the remote left ventricle (LV) following myocardial infarction (MI). Supplemental glutamine improves LV function following MI while inhibiting glutamine metabolism with BPTES worsens LV function. Supplemental glutamine or BPTES does not impact macrophage immunometabolic phenotypes after MI.

Novel Cardiokine GDF3 Predicts Adverse Fibrotic Remodeling After Myocardial Infarction.

BACKGROUND: Myocardial infarction (MI) induces a repair response that ultimately generates a stable fibrotic scar. Although the scar prevents cardiac rupture, an excessive profibrotic response impairs optimal recovery by promoting the development of noncontractile fibrotic areas. The mechanisms that lead to cardiac fibrosis are diverse and incompletely characterized. We explored whether the expansion of cardiac fibroblasts after MI can be regulated through a paracrine action of cardiac stromal cells. METHODS: We performed a bioinformatic secretome analysis of cardiac stromal PW1+ cells isolated from normal and post-MI mouse hearts to identify novel secreted proteins. Functional assays were used to screen secreted proteins that promote fibroblast proliferation. The expressions of candidates were subsequently analyzed in mouse and human hearts and plasmas. The relationship between levels of circulating protein candidates and adverse post-MI cardiac remodeling was examined in a cohort of 80 patients with a first ST-segment-elevation MI and serial cardiac magnetic resonance imaging evaluations. RESULTS: Cardiac stromal PW1+ cells undergo a change in paracrine behavior after MI, and the conditioned media from these cells induced a significant increase in the proliferation of fibroblasts. We identified a total of 12 candidates as secreted proteins overexpressed by cardiac PW1+ cells after MI. Among these factors, GDF3 (growth differentiation factor 3), a member of the TGF-ß (transforming growth factor-ß) family, was markedly upregulated in the ischemic hearts. Conditioned media specifically enriched with GDF3 induced fibroblast proliferation at a high level by stimulation of activin-receptor-like kinases. In line with the secretory nature of this protein, we next found that GDF3 can be detected in mice and human plasma samples, with a significant increase in the days after MI. In humans, higher GDF3 circulating levels (measured in the plasma at day 4 after MI) were significantly associated with an increased risk of adverse remodeling 6 months after MI (adjusted odds ratio, 1.76 [1.03-3.00]; P=0.037), including lower left ventricular ejection fraction and a higher proportion of akinetic segments. CONCLUSIONS: Our findings define a mechanism for the profibrotic action of cardiac stromal cells through secreted cardiokines, such as GDF3, a candidate marker of adverse fibrotic remodeling after MI. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT01113268.

Characterizing the influence of cardiorespiratory fitness on left atrial size and function in the general population.

Increased left atrial (LA) size and reduced LA function have been associated with heart failure and atrial fibrillation (AF) in at-risk populations. However, atrial remodeling has also been associated with exercise training and the relationship between fitness, LA size, and function has not been defined across the fitness spectrum. In a cross-sectional study of 559 ostensibly healthy participants, comprising 304 males (mean age, 46 ± 20 yr) and 255 females (mean age, 47 ± 15 yr), we sought to define the relationship between cardiorespiratory fitness (CRF), LA size, and function. We also aimed to interrogate sex differences in atrial factors influencing CRF. Echocardiographic measures included biplane measures of LA volumes indexed to body surface area (LAVi) and atrial deformation using two-dimensional speckle tracking. CRF was measured as peak oxygen consumption (V̇o2peak) during cardiopulmonary exercise testing (CPET). Using multivariable regression, age, sex, weight, and LAVi (P < 0.001 for all) predicted V̇o2peak (P < 0.001, R2 = 0.66 for combined model). After accounting for these variables, heart rate reserve added strength to the model (P < 0.001, R2 = 0.74) but LA strain parameters did not predict V̇o2peak. These findings add important nuance to the perception that LA size is a marker of cardiac pathology. LA size should be considered in the context of fitness, and it is likely that the adverse prognostic associations of increased LA size may be confined to those with LA enlargement and low fitness.NEW & NOTEWORTHY Left atrial (LA) structure better predicts cardiorespiratory fitness (CRF) than LA function. LA function adds little statistical value to predictive models of peak oxygen uptake (V̇o2peak) in healthy individuals, suggesting limited discriminatory for CRF once LA size is factored. In the wider population of ostensibly healthy individuals, the association between increased LA volume and higher CRF provides an important counter to the association between atrial enlargement and heart failure symptoms in those with cardiac pathology.

Repeat administration of human umbilical cord mesenchymal stem cells improves left ventricular diastolic function in mice with heart failure with preserved ejection fraction.

Currently, no therapy is proven to effectively improve heart failure with preserved ejection fraction (HFpEF). Although stem cell therapy has demonstrated promising results in treating ischemic heart disease, the effectiveness of treating HFpEF with human umbilical cord mesenchymal stem cells (hucMSCs) remains unclear. To answer this question, we administered hucMSCs intravenously (i.v.), either once or repetitively, in a mouse model of HFpEF induced by a high-fat diet and NG-nitroarginine methyl ester hydrochloride. hucMSC treatment improved left ventricular diastolic dysfunction, reduced heart weight and pulmonary edema, and attenuated cardiac modeling (inflammation, interstitial fibrosis, and hypertrophy) in HFpEF mice. Repeat hucMSC administration had better outcomes than a single injection. In vitro, hucMSC culture supernatants reduced maladaptive remodeling in neonatal-rat cardiomyocytes. Ribonucleic acid sequencing and protein level analysis of left ventricle (LV) tissues suggested that hucMSCs activated the protein kinase B (Akt)/forkhead box protein O1 (FoxO1) signaling pathway to treat HFpEF. Inhibition of this pathway reversed the efficacy of hucMSC treatment. In conclusion, these findings indicated that hucMSCs could be a viable therapeutic option for HFpEF.

Mesenchymal stem cells arouse myocardial NAD+ metabolism to alleviate microgravity-induced cardiac dysfunction.

After prolonged space operations, astronauts showed maladaptive atrophy within mostly left-ventricular myocardium, resulting in cardiac dysfunction. However, the mechanism of cardiac dysfunction under microgravity conditions is unclear, and the relevant prevention and treatment measures also need to be explored. Through simulating the microgravity environment with a tail suspension (TS) model, we found that long-term exposure to microgravity promotes aging of mouse hearts, which is closely related to cardiac dysfunction. The intravenous administration of adipose-derived mesenchymal stem cells (ADSCs) emerged preventive and therapeutic effect against myocardial senescence and the decline in cardiac function. Plasma metabolomics analysis suggests the loss of NAD+ in TS mice and motivated myocardial NAD + metabolism and utilization in ADSCs-treated mice, likely accounting for ADSCs' function. Oral administration of nicotinamide mononucleotide (NMN, a NAD + precursor) showed similar therapeutic effect to ADSCs treatment. Collectively, these data implicate the effect of ADSCs in microgravity-induced cardiac dysfunction and provide new therapeutic ideas for aging-related maladaptive cardiac remodeling.

Disruption of the interaction between caveolae and Piezo1 promotes pressure overload-induced cardiac remodeling.

Piezo1 channels are activated by mechanical stress and play a significant role in cardiac hypertrophy and fibrosis. However, the molecular mechanisms underlying Piezo1 activation on the cell membrane following pressure overload remain unclear. Caveolae are known to mitigate mechanical forces and regulate Piezo1 function. Therefore, this study aimed to investigate the interaction between caveolae and Piezo1 in the development of pressure overload-induced cardiac remodeling. We observed reduced colocalization between Piezo1 and Caveolin-3 in hypertrophic cardiomyocytes following abdominal aortic constriction and Angiotensin-II treatment, accompanied by increased Piezo1 function and expression. Furthermore, enhanced Piezo1 function was also noted upon caveolae disruption using methyl-beta-cyclodextrin (mßCD). Thus, our findings suggested that pressure overload led to Piezo1 translocation from caveolae, thereby augmenting its function and expression, which may contribute to cardiac remodeling.

Chronic kidney disease activates the HDAC6-inflammatory axis in the heart and contributes to myocardial remodeling in mice: inhibition of HDAC6 alleviates chronic kidney disease-induced myocardial remodeling.

Chronic kidney disease (CKD) adversely affects the heart. The underlying mechanism and the interplay between the kidney and the heart are still obscure. We examined the cardiac effect using the unilateral ureteral obstruction (UUO)-induced CKD pre-clinical model in mice. Echocardiography, histopathology of the heart, myocardial mRNA expression of ANP and BNP, the extent of fibrotic (TGF-ß, α-SMA, and collagen I) and epigenetic (histone deacetylases, namely HDAC3, HDAC4, and HDAC6) proteins, and myocardial inflammatory response were assessed. Six weeks of post-UUO surgery, we observed a compromised left-ventricular wall thickness and signs of cardiac hypertrophy, accumulation of fibrosis associated, and inflammatory proteins in the heart. In addition, we observed a perturbation of epigenetic proteins, especially HDAC3, HDAC4, and HDAC6, in the heart. Pharmacological inhibition of HDAC6 using ricolinostat (RIC) lessened cardiac damage and improved left-ventricular wall thickness. The RIC treatment substantially restored the serum cardiac injury markers, namely creatine kinase-MB and lactate dehydrogenase (LDH) activities, ANP and BNP mRNA expression, and heart histological changes. The extent of myocardial fibrotic proteins, phospho-NF-κB (p65), and pro-inflammatory cytokines (TNF-α, IL-18, and IL-1ß) were significantly decreased in the RIC treatment group. Further findings revealed the CKD-induced infiltration of CD3, CD8a, CD11c, and F4/80 positive inflammatory cells in the heart. Treatment with RIC substantially reduced the myocardial infiltration of these inflammatory cells. From these findings, we believe that CKD-induced myocardial HDAC6 perturbation has a deteriorative effect on the heart, and inhibition of HDAC6 can be a promising approach to alleviate CKD-induced myocardial remodeling.

Macrophage-based therapeutic approaches for cardiovascular diseases.

Despite the advances in treatment options, cardiovascular disease (CVDs) remains the leading cause of death over the world. Chronic inflammatory response and irreversible fibrosis are the main underlying pathophysiological causes of progression of CVDs. In recent decades, cardiac macrophages have been recognized as main regulatory players in the development of these complex pathophysiological conditions. Numerous approaches aimed at macrophages have been devised, leading to novel prospects for therapeutic interventions. Our review covers the advancements in macrophage-centric treatment plans for various pathologic conditions and examines the potential consequences and obstacles of employing macrophage-targeted techniques in cardiac diseases.

LIPCAR levels in plasma-derived extracellular vesicles is associated with left ventricle remodeling post-myocardial infarction.

BACKGROUND: Long Intergenic noncoding RNA predicting CARdiac remodeling (LIPCAR) is a long noncoding RNA identified in plasma of patients after myocardial infarction (MI) to be associated with left ventricle remodeling (LVR). LIPCAR was also shown to be a predictor of early death in heart failure (HF) patients. However, no information regarding the expression of LIPCAR and its function in heart as well as the mechanisms involved in its transport to the circulation is known. The aims of this study are (1) to characterize the transporter of LIPCAR from heart to circulation; (2) to determine whether LIPCAR levels in plasma isolated-extracellular vesicles (EVs) reflect the alteration of its expression in total plasma and could be used as biomarkers of LVR post-MI. METHODS: Since expression of LIPCAR is restricted to human species and the limitation of availability of cardiac biopsy samples, serum-free conditioned culture media from HeLa cells were first used to characterize the extracellular transporter of LIPCAR before validation in EVs isolated from human cardiac biopsies (non-failing and ischemic HF patients) and plasma samples (patients who develop or not LVR post-MI). Differential centrifugation at 20,000g and 100,000g were performed to isolate the large (lEVs) and small EVs (sEVs), respectively. Western blot and nanoparticle tracking (NTA) analysis were used to characterize the isolated EVs. qRT-PCR analysis was used to quantify LIPCAR in all samples. RESULTS: We showed that LIPCAR is present in both lEVs and sEVs isolated from all samples. The levels of LIPCAR are higher in lEVs compared to sEVs isolated from HeLa conditioned culture media and cardiac biopsies. No difference of LIPCAR expression was observed in tissue or EVs isolated from cardiac biopsies obtained from ischemic HF patients compared to non-failing patients. Interestingly, LIPCAR levels were increased in lEVs and sEVs isolated from MI patients who develop LVR compared to patients who did not develop LVR. CONCLUSION: Our data showed that large EVs are the main extracellular vesicle transporter of LIPCAR from heart into the circulation independently of the status, non-failing or HF, in patients. The levels of LIPCAR in EVs isolated from plasma could be used as biomarkers of LVR in post-MI patients.

The role of periostin in cardiac fibrosis.

Cardiac fibrosis, which is the buildup of proteins in the connective tissues of the heart, can lead to end-stage extracellular matrix (ECM) remodeling and ultimately heart failure. Cardiac remodeling involves changes in gene expression in cardiac cells and ECM, which significantly leads to the morbidity and mortality in heart failure. However, despite extensive research, the elusive intricacies underlying cardiac fibrosis remain unidentified. Periostin, an extracellular matrix (ECM) protein of the fasciclin superfamily, acts as a scaffold for building complex architectures in the ECM, which improves intermolecular interactions and augments the mechanical properties of connective tissues. Recent research has shown that periostin not only contributes to normal ECM homeostasis in a healthy heart but also serves as a potent inducible regulator of cellular reorganization in cardiac fibrosis. Here, we reviewed the constitutive domain of periostin and its interaction with other ECM proteins. We have also discussed the critical pathophysiological functions of periostin in cardiac remodeling mechanisms, including two distinct yet potentially intertwined mechanisms. Furthermore, we will focus on the intrinsic complexities within periostin research, particularly surrounding the contentious issues observed in experimental findings.

SAA1 deficiency alleviates cardiac remodeling by inhibiting NF-κB/p38/JNK and TGFß/Smad pathways.

Heart failure (HF) is the end stage of the progression of many cardiovascular diseases. Cardiac remodeling is the main pathophysiological process of cardiac function deterioration in HF patients. Inflammation is a key factor that stimulates cardiomyocyte hypertrophy, fibroblast proliferation, and transformation leading to myocardial remodeling, which severity is significantly related to the prognosis of patients. SAA1 (Serum amyloid A1) is a lipid-binding protein that was an important regulator involved in inflammation, whose biological functions in the heart remain rarely known. In this research, we intended to test the role of SAA1 in SAA1-deficient (SAA1-/- ), and wild-type mice were exposed to transverse aortic banding surgery to establish the model of cardiac remodeling. Besides, we assessed the functional effects of SAA1 on cardiac hypertrophy and fibrosis. The expression of SAA1 was increased in the mice transverse aortic banding model induced by pressure overload. After 8 weeks of transverse aortic banding, SAA1-/- mice displayed a lower level of cardiac fibrosis than wild-type mice, but did not significantly influence the cardiomyocyte hypertrophy. In addition, there was also no significant difference in cardiac fibrosis severity between wild-type-sham and knockout-sham mice. These findings are the first to reveal SAA1 absence hinders cardiac fibrosis after 8 weeks of transverse aortic banding. Furthermore, SAA1 deficiency had no significant effect on cardiac fibrosis and hypertrophy in the sham group in this study.

TRIM35 triggers cardiac remodeling by regulating SLC7A5-mediated amino acid transport and mTORC1 activation in fibroblasts.

BACKGROUND: Cardiac maladaptive remodeling is one of the leading causes of heart failure with highly complicated pathogeneses. The E3 ligase tripartite motif containing 35 (TRIM35) has been identified as a crucial regulator governing cellular growth, immune responses, and metabolism. Nonetheless, the role of TRIM35 in fibroblasts in cardiac remodeling remains elusive. METHODS: Heart tissues from human donors were used to verify tissue-specific expression of TRIM35. Fibroblast-specific Trim35 gene knockout mice (Trim35cKO) were used to investigate the function of TRIM35 in fibroblasts. Cardiac function, morphology, and molecular changes in the heart tissues were analyzed after transverse aortic constriction (TAC) surgery. The mechanisms by which TRIM35 regulates fibroblast phenotypes were elucidated using liquid chromatography-tandem mass spectrometry (LC-MS/MS) and RNA sequencing (RNA-Seq). These findings were further validated through the use of adenoviral and adeno-associated viral transfection systems, as well as the mTORC1 inhibitor Rapamycin. RESULTS: TRIM35 expression is primarily up-regulated in cardiac fibroblasts in both murine and human fibrotic hearts, and responds to TGF-ß1 stimulation. Specific deletion of TRIM35 in cardiac fibroblasts significantly improves cardiac fibrosis and hypertrophy. Consistently, the overexpression of TRIM35 promotes fibroblast proliferation, migration, and differentiation. Through paracrine signaling, it induces hypertrophic growth of cardiomyocytes. Mechanistically, we found that TRIM35 interacts with, ubiquitinates, and up-regulates the amino acid transporter SLC7A5, which enhances amino acid transport and activates the mTORC1 signaling pathway. Furthermore, overexpression of SLC7A5 significantly reverses the reduced cardiac fibrosis and hypertrophy caused by conditional knockout of TRIM35. CONCLUSION: Our findings demonstrate a novel role of fibroblast-TRIM35 in cardiac remodeling and uncover the mechanism underlying SLC7A5-mediated amino acid transport and mTORC1 activation. These results provide a potential novel therapeutic target for treating cardiac remodeling.

ER stress improvement by aerobic training or enalapril differently ameliorates pathological cardiac remodeling in obese mice.

Overactivation of the classic arm of the renin-angiotensin system (RAS) is one of the main mechanisms involved in obesity-related cardiac remodeling, and a possible relationship between RAS and ER stress in the cardiovascular system have been described. Thus, the aim of this study is to evaluate if activating the protective arm of the RAS by ACE inhibition or aerobic exercise training could overturn diet-induced pathological cardiac hypertrophy by attenuating ER stress. Male C57BL/6 mice were fed a control (SC) or a high-fat diet (HF) for 16 weeks. In the 8th week, HF-fed animals were randomly divided into HF, enalapril treatment (HF-En), and aerobic exercise training (HF-Ex) groups. Body mass (BM), food and energy intake, plasma analyzes, systolic blood pressure (SBP), physical conditioning, and plasma ACE and ACE2 activity were evaluated. Cardiac morphology, and protein expression of hypertrophy, cardiac metabolism, RAS, and ER stress markers were assessed. Data presented as mean ± standard deviation and analyzed by one-way ANOVA with Holm-Sidak post-hoc. HF group had increased BM and SBP, and developed pathological concentric cardiac hypertrophy, with overactivation of the classic arm of the RAS, and higher ER stress. Both interventions reverted the increase in BM, and SBP, and favored the protective arm of the RAS. Enalapril treatment improved pathological cardiac hypertrophy with partial reversal of the concentric pattern, and slightly attenuated cardiac ER stress. In contrast, aerobic exercise training induced physiological eccentric cardiac hypertrophy, and fully diminished ER stress.