Pathological Cardiac Remodeling Research Articles

RNA binding proteins as mediators of pathological cardiac remodeling

RNA binding proteins (RBPs) play a central in the post-transcriptional regulation of gene expression, which can account for up to 50% of all variations in protein expression within a cell. Following their binding to target RNAs, RBPs most typically confer changes in gene expression through modulation of alternative spicing, RNA stabilization/degradation, or ribosome loading/translation rate. All of these post-transcriptional regulatory processes have been shown to play a functional role in pathological cardiac remodeling, and a growing body of evidence is beginning to identify the mechanistic contribution of individual RBPs and their cardiac RNA targets. This review highlights the mechanisms of RBP-dependent post-transcriptional gene regulation in cardiomyocytes and fibroblasts and our current understanding of how RNA binding proteins functionally contribute to pathological cardiac remodeling.

LncRNA ZNF593-AS inhibits cardiac hypertrophy and myocardial remodeling by upregulating Mfn2 expression.

lncRNA ZNF593 antisense (ZNF593-AS) transcripts have been implicated in heart failure through the regulation of myocardial contractility. The decreased transcriptional activity of ZNF593-AS has also been detected in cardiac hypertrophy. However, the function of ZNF593-AS in cardiac hypertrophy remains unclear. Herein, we report that the expression of ZNF593-AS reduced in a mouse model of left ventricular hypertrophy and cardiomyocytes in response to treatment with the hypertrophic agonist phenylephrine (PE). In vivo, ZNF593-AS aggravated pressure overload-induced cardiac hypertrophy in knockout mice. By contrast, cardiomyocyte-specific transgenic mice (ZNF593-AS MHC-Tg) exhibited attenuated TAC-induced cardiac hypertrophy. In vitro, vector-based overexpression using murine or human ZNF593-AS alleviated PE-induced myocyte hypertrophy, whereas GapmeR-induced inhibition aggravated hypertrophic phenotypes. By using RNA-seq and gene set enrichment analyses, we identified a link between ZNF593-AS and oxidative phosphorylation and found that mitofusin 2 (Mfn2) is a direct target of ZNF593-AS. ZNF593-AS exerts an antihypertrophic effect by upregulating Mfn2 expression and improving mitochondrial function. Therefore, it represents a promising therapeutic target for combating pathological cardiac remodeling.

Overexpression of zinc-finger protein 418 inhibits pathological cardiac remodelling after acute myocardial infarction.

Zinc-finger protein 418 (ZNF418) has been confirmed to be expressed in myocardial tissue. However, the role and mechanism of ZNF418 in pathological myocardial remodelling after myocardial infarction (MI) have not been reported. This study was to elucidate the effect and mechanism of ZNF418 on ventricular remodelling after MI in mice. MI mice and H9c2 cardiomyocytes were used to conduct in vivo and in vitro experiments, respectively. ZNF418 expression was regulated by adeno-associated virus 9 and adenovirus vectors. Pathological analysis, echocardiography, and molecular analysis were performed. ZNF418 was down-regulated in the left ventricular tissues of post-MI mice. In contrast, ZNF418 overexpression decreased mortality and improved cardiac function in MI mice. The MI mice exhibited a significantly increased cross-sectional area of myocardial cells and elevated protein expression levels of myocardial hypertrophy markers ANP, BNP, and β-MHC (all P<0.05). Moreover, a significantly increased area of myocardial fibrosis and protein expression levels of myocardial fibrosis markers collagen I, collagen III, and CTGF were observed in MI mice (all P<0.05) in MI mice. All of the above negative effects in MI mice were ameliorated in ZNF418 overexpressed mice (all P<0.05). Mechanistically, ZNF418 overexpression inhibited the activation of the MAPK signalling pathway, as evidenced by the in vivo and in vitro experiments. Overexpression of ZNF418 could improve cardiac function and inhibit pathological cardiac remodelling by inhibiting the MAPK signalling pathway in post-MI mice.

Correlation of circulating fibroblast growth factor 21 levels with inflammatory factors and the degree of coronary artery stenosis in patients with acute myocardial infarction

BackgroundFibroblast growth factor 21 (FGF21) is a secreted protein that plays an important role in atherosclerosis and pathological cardiac remodeling. However, the correlation between FGF21 and the degree of coronary artery stenosis and its potential role in acute myocardial infarction (AMI) remain unclear. We examined whether changes in FGF21 levels in AMI correlate with the degree of coronary artery stenosis and the levels of inflammatory factors, and preliminarily investigated the effects of FGF21 on inflammatory factor levels and myocardial injury in rats with AMI. MethodsSerum levels of FGF21 and inflammatory factors in the AMI group and control group were measured, and the correlation between FGF21 and clinical indicators and inflammatory factors was analyzed. The effects of FGF21 on cardiac function and inflammatory response were evaluated through echocardiography and measurement of inflammatory factors. ResultsMultivariate logistic regression analysis showed that neutrophil percentage (NEUT%, odds ratio [OR]: 1.232; 95 % confidence interval [CI]: 1.028–1.477; p = 0.024) and FGF21 levels (OR: 2.063; 95 % CI: 1.187–3.586; p = 0.01) had independent effects on AMI. Spearman's rank correlation test showed that FGF21 levels were positively correlated with leukocyte count, NEUT%, neutrophil count, neutrophil to lymphocyte ratio, C-reactive protein, interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), monocyte chemotactic protein-1 (MCP-1) and Gensini scores (p < 0.01), but negatively correlated with lymphocyte count (p < 0.01). FGF21 levels in myocardial tissues and serum levels of FGF21, IL-6, TNF-a, and MCP-1 were significantly higher in AMI rats than in the sham-operated group (p < 0.01). After overexpression of FGF21, serum levels of IL-6, TNF-a, and MCP-1 in rats were significantly decreased (p < 0.01), and cardiac function improved significantly. ConclusionsFGF21 levels were independently associated with AMI and may be related to the severity of coronary artery stenosis. Overexpression of FGF21 reduced serum inflammatory factor levels and improved cardiac function in AMI rats.

Protein phosphatase 2A anchoring disruptor gene therapy for familial dilated cardiomyopathy

Familial Dilated Cardiomyopathy is a prevalent cause of heart failure that results from the mutation of genes encoding proteins of diverse function. Despite modern therapy, Dilated Cardiomyopathy typically has a poor outcome and is the leading cause of cardiac transplantation. The phosphatase PP2A at cardiomyocyte perinuclear mAKAPβ signalosomes promotes pathological eccentric cardiac remodeling, as is characteristic of Dilated Cardiomyopathy. Displacement of PP2A from mAKAPβ, inhibiting PP2A function in that intracellular compartment, can be achieved by expression of a mAKAPβ-derived PP2A binding domain-derived peptide. To test whether PP2A anchoring disruption would be effective at preventing Dilated Cardiomyopathy-associated cardiac dysfunction, the adeno-associated virus gene therapy vector AAV9sc.PBD was devised to express the disrupting peptide in cardiomyocytes in vivo. Proof-of-concept is now provided that AAV9sc.PBD improves the cardiac structure and function of a cardiomyopathy mouse model involving transgenic expression of a mutant α-tropomyosin E54K Tpm1 allele, while AAV9sc.PBD has no effect on normal non-transgenic mice. At the cellular level, AAV9sc.PBD restores cardiomyocyte morphology and gene expression in the mutant Tpm1 mouse. As the mechanism of AAV9sc.PBD action suggests potential efficacy in Dilated Cardiomyopathy regardless of the underlying etiology, these data support the further testing of AAV9sc.PBD as a broad-based treatment for Dilated Cardiomyopathy.

α-Melanocyte-stimulating hormone alleviates pathological cardiac remodeling via melanocortin 5 receptor

α-Melanocyte-stimulating hormone (α-MSH) regulates diverse physiological functions by activating melanocortin receptors (MC-R). However, the role of α-MSH and its possible target receptors in the heart remain completely unknown. Here we investigate whether α-MSH could be involved in pathological cardiac remodeling. We found that α-MSH was highly expressed in the mouse heart with reduced ventricular levels after transverse aortic constriction (TAC). Administration of a stable α-MSH analog protected mice against TAC-induced cardiac hypertrophy and systolic dysfunction. In vitro experiments revealed that MC5-R in cardiomyocytes mediates the anti-hypertrophic signaling of α-MSH. Silencing of MC5-R in cardiomyocytes induced hypertrophy and fibrosis markers in vitro and aggravated TAC-induced cardiac hypertrophy and fibrosis in vivo. Conversely, pharmacological activation of MC5-R improved systolic function and reduced cardiac fibrosis in TAC-operated mice. In conclusion, α-MSH is expressed in the heart and protects against pathological cardiac remodeling by activating MC5-R in cardiomyocytes. These results suggest that analogs of naturally occurring α-MSH, that have been recently approved for clinical use and have agonistic activity at MC5-R, may be of benefit in treating heart failure.

Overexpressing of the GIPC1 protects against pathological cardiac remodelling

ObjectivePathological 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 β-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 β1-adrenergic receptor (β1-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. MethodsPathological 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. ResultsGIPC1 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 β1-adrenergic receptor and stabilised its expression by preventing its ubiquitination and degradation, maintaining the balance of β1-adrenergic receptor/β2-adrenergic receptor, and inhibiting hyperactivation of the mitogen-activated protein kinase signalling pathway. ConclusionsThese results suggested that GIPC1 plays a cardioprotective role and is a promising therapeutic target for the treatment of cardiac remodelling and heart failure.

Cardiac transcriptomic changes induced by early CKD in mice reveal novel pathways involved in the pathogenesis of Cardiorenal syndrome type 4

BackgroundCardiorenal syndrome (CRS) type 4 is prevalent among the chronic kidney disease (CKD) population, with many patients dying from cardiovascular complications. However, limited data regarding cardiac transcriptional changes induced early by CKD is available. MethodsWe used a murine unilateral ureteral obstruction (UUO) model to evaluate renal damage, cardiac remodeling, and transcriptional regulation at 21 days post-surgery through histological analysis, RT-qPCR, RNA-seq, and bioinformatics. ResultsUUO leads to significant kidney injury, low uremia, and pathological cardiac remodeling, evidenced by increased collagen deposition and smooth muscle alpha-actin 2 expression. RNA-seq analysis identified 76 differentially expressed genes (DEGs) in UUO hearts. Upregulated DEGs were significantly enriched in cell cycle and cell division pathways, immune responses, cardiac repair, inflammation, proliferation, oxidative stress, and apoptosis. Gene Set Enrichment Analysis further revealed mitochondrial oxidative bioenergetic pathways, autophagy, and peroxisomal pathways are downregulated in UUO hearts. Vimentin was also identified as an UUO-upregulated transcript. ConclusionsOur results emphasize the relevance of extensive transcriptional changes, mitochondrial dysfunction, homeostasis deregulation, fatty-acid metabolism alterations, and vimentin upregulation in CRS type 4 development.

Adeno-associated virus-based approach for genetic modification of cardiac fibroblasts in adult rat hearts.

Cardiac fibroblasts (CFs) are an attractive target for reducing pathological cardiac remodeling, and understanding the underlying mechanisms of these processes is the key to develop successful therapies for treating the pressure-overloaded heart. CF-specific knockout (KO) mouse lines with a Cre recombinase under the control of human TCF21 (hTCF21) promoter and/or an adeno-associated virus serotype 9 (AAV9)-hTCF21 system provide a powerful tool for understanding CF biology invivo. Although a variety of rat disease models are vital for the research of cardiac fibrosis similar to mouse models, there are few rat models that employ cardiac cell-specific conditional gene modification, which has hindered the development and translational relevance of cardiac disease models. In addition, to date, there are no reports of gene manipulation specifically in rat CFs invivo. Here, we report a simplified CF-specific rat transgenic model using an AAV9-hTCF21 system that achieved a CF-specific expression of transgene in adult rat hearts. Moreover, we successfully applied this approach to specifically manipulate mitochondrial morphology in quiescent CFs. In summary, this model will allow us to develop fast and simple rat CF-specific transgenic models for studying cardiovascular diseases invivo.

TEA domain transcription factor 1 (TEAD1) induces cardiac fibroblasts cells remodeling through BRD4/Wnt4 pathway

Cardiac fibroblasts (CFs) are the primary cells tasked with depositing and remodeling collagen and significantly associated with heart failure (HF). TEAD1 has been shown to be essential for heart development and homeostasis. However, fibroblast endogenous TEAD1 in cardiac remodeling remains incompletely understood. Transcriptomic analyses revealed consistently upregulated cardiac TEAD1 expression in mice 4 weeks after transverse aortic constriction (TAC) and Ang-II infusion. Further investigation revealed that CFs were the primary cell type expressing elevated TEAD1 levels in response to pressure overload. Conditional TEAD1 knockout was achieved by crossing TEAD1-floxed mice with CFs- and myofibroblasts-specific Cre mice. Echocardiographic and histological analyses demonstrated that CFs- and myofibroblasts-specific TEAD1 deficiency and treatment with TEAD1 inhibitor, VT103, ameliorated TAC-induced cardiac remodeling. Mechanistically, RNA-seq and ChIP-seq analysis identified Wnt4 as a novel TEAD1 target. TEAD1 has been shown to promote the fibroblast-to-myofibroblast transition through the Wnt signalling pathway, and genetic Wnt4 knockdown inhibited the pro-transformation phenotype in CFs with TEAD1 overexpression. Furthermore, co-immunoprecipitation combined with mass spectrometry, chromatin immunoprecipitation, and luciferase assays demonstrated interaction between TEAD1 and BET protein BRD4, leading to the binding and activation of the Wnt4 promoter. In conclusion, TEAD1 is an essential regulator of the pro-fibrotic CFs phenotype associated with pathological cardiac remodeling via the BRD4/Wnt4 signalling pathway.

Protective Effect of CD137 Deficiency against Post-infarction Cardiac Fibrosis and Adverse Cardiac Remodeling via ERK1/2 Signaling Pathways.

Myocardial fibrosis, a common complication of myocardial infarction (MI), is characterized by excessive collagen deposition and can result in impaired cardiac function. The specific role of CD137 in the development of post-MI myocardial fibrosis remains unclear. Thus, this study aimed to elucidate the effects of CD137 signaling using CD137 knockout mice and in vitro experiments. CD137 expression levels progressively increased in the heart following MI, particularly in myofibroblast, which play a key role in fibrosis. Remarkably, CD137 knockout mice exhibited improved cardiac function and reduced fibrosis compared to wild-type mice at day 28 post-MI. The use of Masson's trichrome and picrosirius red staining demonstrated a reduction in the infarct area and collagen volume fraction in CD137 knockout mice. Furthermore, the expression of alpha-smooth muscle actin (α-SMA) and collagen I, key markers of fibrosis, was decreased in heart tissues lacking CD137. In vitro experiments supported these findings, as CD137 depletion attenuated cardiac fibroblast differentiation, and migration, and collagen I synthesis. Additionally, the administration of CD137L recombinant protein further promoted α-SMA expression and collagen I synthesis, suggesting a pro-fibrotic effect. Notably, the application of an inhibitor targeting the extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathway attenuated the pro-fibrotic effects of CD137L. To conclude, this study provides evidence that CD137 plays a significant role in promoting myocardial fibrosis after MI. Inhibition of CD137 signaling pathways may hold therapeutic potential for mitigating pathological cardiac remodeling and improving post-MI cardiac function.

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 16weeks. 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.

Crosstalk between endothelial cells with a non-canonical EndoMT phenotype and cardiomyocytes/fibroblasts via IGFBP5 aggravates TAC-induced cardiac dysfunction

Heart failure (HF) is a complex chronic condition characterized by structural and functional impairments. The differentiation of endothelial cells into myofibroblasts (EndoMT) in response to cardiac fibrosis is controversial, and the relative contribution of endothelial plasticity remains to be explored. Single-cell RNA sequencing was used to identify endothelial cells undergoing fibrotic differentiation within 2 weeks of transverse aortic constriction (TAC). This subset of endothelial cells transiently expressed fibrotic genes but had low expression of alpha-smooth muscle actin, indicating a non-canonical EndoMT, which we named a transient fibrotic-like phenotype (EndoFP). The role of EndoFP in pathological cardiac remodeling may be correlated with increased levels of osteopontin. Cardiomyocytes and fibroblasts co-cultured with EndoFP exhibited heightened pro-hypertrophic and pro-fibrotic effects. Mechanistically, we found that the upregulated expression of insulin-like growth factor-binding protein 5 may be a key mediator of EndoFP-induced cardiac dysfunction. Furthermore, our findings suggested that Rab5a is a novel regulatory gene involved in the EndoFP process. Our study suggests that the specific endothelial subset identified in TAC-induced pressure overload plays a critical role in the cellular interactions that lead to cardiac fibrosis and hypertrophy. Additionally, our findings provide insight into the mechanisms underlying EndoFP, making it a potential therapeutic target for early heart failure.

Aerobic interval training preconditioning protocols inhibit isoproterenol-induced pathological cardiac remodeling in rats: Implications on oxidative balance, autophagy, and apoptosis

This study aimed to investigate the potential cardioprotective effects of moderate and high-intensity aerobic interval training (MIIT and HIIT) preconditioning. The focus was on histological changes, pro-oxidant-antioxidant balance, autophagy initiation, and apoptosis in myocardial tissue incited by isoproterenol-induced pathological cardiac remodeling (ISO-induced PCR). Male Wistar rats were randomly divided into control (n ​= ​6), ISO (n ​= ​8), MIIT (n ​= ​4), HIIT (n ​= ​4), MIIT ​+ ​ISO (n ​= ​8), and HIIT ​+ ​ISO (n ​= ​8) groups. The MIIT and HIIT protocols were administered for 10 weeks, followed by the induction of cardiac remodeling using subcutaneous injection of ISO (100 ​mg/kg for two consecutive days). Alterations in heart rate (HR), mean arterial pressure (MAP), rate pressure product (RPP), myocardial oxygen consumption (MV˙O2), cardiac hypertrophy, histopathological changes, pro-oxidant-antioxidant balance, autophagy biomarkers (Beclin-1, Atg7, p62, LC3 I/II), and apoptotic cell distribution were measured. The findings revealed that the MIIT ​+ ​ISO and HIIT ​+ ​ISO groups demonstrated diminished myocardial damage, hemorrhage, immune cell infiltration, edema, necrosis, and apoptosis compared to ISO-induced rats. MIIT and HIIT preconditioning mitigated HR, enhanced MAP, and preserved MV˙O2 and RPP. The pro-oxidant-antioxidant balance was sustained in both MIIT ​+ ​ISO and HIIT ​+ ​ISO groups, with MIIT primarily inhibiting pro-apoptotic autophagy progression through maintaining pro-oxidant-antioxidant balance, and HIIT promoting pro-survival autophagy. The results demonstrated the beneficial effects of both MIIT and HIIT as AITs preconditioning in ameliorating ISO-induced PCR by improving exercise capacity, hemodynamic parameters, and histopathological changes. Some of these protective effects can be attributed to the modulation of cardiac apoptosis, autophagy, and oxidative stress.

C-terminal fragment of fibroblast growth factor 23 improves heart function in murine models of high intact fibroblast growth factor 23.

Cardiovascular disease (CVD) is the major cause of death in chronic kidney disease (CKD) and is associated with high circulating fibroblast growth factor (FGF)23 levels. It is unresolved whether high circulating FGF23 is a mere biomarker or pathogenically contributes to cardiomyopathy. It is also unknown whether the C-terminal FGF23 peptide (cFGF23), a natural FGF23 antagonist proteolyzed from intact FGF23 (iFGF23), retards CKD progression and improves cardiomyopathy. We addressed these questions in three murine models with high endogenous FGF23 and cardiomyopathy. First, we examined wild-type (WT) mice with CKD induced by unilateral ischemia-reperfusion and contralateral nephrectomy followed by a high-phosphate diet. These mice were continuously treated with intraperitoneal implanted osmotic minipumps containing either iFGF23 protein to further escalate FGF23 bioactivity, cFGF23 peptide to block FGF23 signaling, vehicle, or scrambled peptide as negative controls. Exogenous iFGF23 protein given to CKD mice exacerbated pathological cardiac remodeling and CKD progression, whereas cFGF23 treatment improved heart and kidney function, attenuated fibrosis, and increased circulating soluble Klotho. WT mice without renal insult placed on a high-phosphate diet and homozygous Klotho hypomorphic mice, both of whom develop moderate CKD and clear cardiomyopathy, were treated with cFGF23 or vehicle. Mice treated with cFGF23 in both models had improved heart and kidney function and histopathology. Taken together, these data indicate high endogenous iFGF23 is not just a mere biomarker but pathogenically deleterious in CKD and cardiomyopathy. Furthermore, attenuation of FGF23 bioactivity by cFGF23 peptide is a promising therapeutic strategy to protect the kidney and heart from high FGF23 activity.NEW & NOTEWORTHY There is a strong correlation between cardiovascular morbidity and high circulating fibroblast growth factor 23 (FGF23) levels, but causality was never proven. We used a murine chronic kidney disease (CKD) model to show that intact FGF23 (iFGF23) is pathogenic and contributes to both CKD progression and cardiomyopathy. Blockade of FGF23 signaling with a natural proteolytic product of iFGF23, C-terminal FGF23, alleviated kidney and cardiac histology, and function in three separate murine models of high endogenous FGF23.

Mac-1 deficiency ameliorates pressure overloaded heart failure through inhibiting macrophage polarization and activation

Persistent pressure overload commonly leads to pathological cardiac hypertrophy and remodeling, ultimately leading to heart failure (HF). Cardiac remodeling is associated with the involvement of immune cells and the inflammatory response in pathogenesis. The macrophage-1 antigen (Mac-1) is specifically expressed on leukocytes and regulates their migration and polarization. Nonetheless, the involvement of Mac-1 in cardiac remodeling and HF caused by pressure overload has not been determined. The Mac-1-knockout (KO) and wild-type (WT) mice were subjected to transverse aortic constriction (TAC) for 6 weeks. Echocardiography and pressure–volume loop assessments were used to evaluate cardiac function, and cardiac remodeling and macrophage infiltration and polarization were estimated by histopathology and molecular techniques. The findings of our study demonstrated that Mac-1 expression was markedly increased in hearts subjected to TAC treatment. Moreover, compared with WT mice, Mac-1-KO mice exhibited dramatically ameliorated TAC-induced cardiac dysfunction, hypertrophy, fibrosis, oxidative stress and apoptosis. The potential positive impacts may be linked to the inhibition of macrophage infiltration and M1 polarization via reductions in NF-kB and STAT1 expression and upregulation of STAT6. In conclusion, this research reveals a new function of Mac-1 deficiency in reducing pathological cardiac remodeling and HF caused by pressure overload. Additionally, inhibiting Mac-1 could be a potential treatment option for patients with HF in a clinical setting.

Pterostilbene attenuates heart failure by inhibiting myocardial ferroptosis through SIRT1/GSK-3β/GPX4 signaling pathway

Sustained myocardial injury due to hypertension and diabetes mellitus leads to production of endogenous reactive oxygen species (ROS) and insufficient myocardial antioxidant capacity, increasing the risk of cardiomyocyte ferroptosis. Ferroptosis is a nonapoptotic form of cell death driven by unrestricted lipid peroxidation. Dysfunction of the glutathione peroxidase 4 (GPX4) antioxidant system also plays an important role in ferroptosis. Cardiomyocyte ferroptosis ultimately leads to myocardial deterioration, such as inflammation, fibrosis, and cardiac remodeling, resulting in structural and functional changes. Pterostilbene (PTS), a demethylated derivative of resveratrol, exhibits strong anti-inflammatory and antioxidative activities. In this study, we used in vitro experiments to explore ferroptosis induced by angiotensin II (Ang II) of primary cardiac myocytes (CMs) and in vivo experiments to prepare a transverse aortic constriction (TAC)-induced cardiac dysfunction mouse model. PTS can significantly ameliorate Ang II-induced cardiomyocyte ferroptosis in vitro and reduce cardiac remodeling, while improving cardiac function in mice after TAC in vivo. Further mechanistic investigations revealed that PTS exerts its protective effect through the SIRT1/GSK-3β/GPX4 pathway. After siRNA-mediated knockdown of SIRT1 or GPX4 in CMs, the protective effects of PTS on cardiomyocytes were abolished. This study provides important theoretical support for the potential of PTS to attenuate pathological cardiac remodeling and heart failure and provides a preliminary exploration of the molecular pathways involved in its protective mechanism.

Fibroblasts and platelets: a face-to-face dialogue at the heart of cardiac fibrosis.

Myocardial fibrosis is a feature found in most cardiac diseases and a key element contributing to heart failure and its progression. It has therefore become a subject of particular interest in cardiac research. Mechanisms leading to pathological cardiac remodeling and heart failure are diverse, including effects on cardiac fibroblasts, the main players in cardiac extracellular matrix synthesis, but also on cardiomyocytes, immune cells, endothelial cells, and more recently, platelets. Although transforming growth factor-β (TGF-β) is a primary regulator of fibrosis development, the cellular and molecular mechanisms that trigger its activation after cardiac injury remain poorly understood. Different types of anti-TGF-β drugs have been tested for the treatment of cardiac fibrosis and have been associated with side effects. Therefore, a better understanding of these mechanisms is of great clinical relevance and could allow us to identify new therapeutic targets. Interestingly, it has been shown that platelets infiltrate the myocardium at an early stage after cardiac injury, producing large amounts of cytokines and growth factors. These molecules can directly or indirectly regulate cells involved in the fibrotic response, including cardiac fibroblasts and immune cells. In particular, platelets are known to be a major source of TGF-β1. In this review, we have provided an overview of the classical cellular effectors involved in the pathogenesis of cardiac fibrosis, focusing on the emergent role of platelets, while discussing opportunities for novel therapeutic interventions.

Protective effects of METRNL overexpression against pathological cardiac remodeling

At present, meteorin-like protein (METRNL) has been proven to be widely expressed in the myocardium and participates in the pathogenic process of various cardiovascular diseases. However, the effects of METRNL on pathological cardiac hypertrophy is still unknown. In the present study, we used a mouse model of transverse aortic constriction (TAC) surgery to mimic pathological cardiac hypertrophy and gene delivery system to overexpress METRNL in vivo. The results showed that METRNL overexpression improved TAC-induced pathological cardiac hypertrophy in mice and neonatal cardiomyocytes. In addition, METRNL overexpression diminished TAC-induced cardiac oxidative damage, inflammation and cardiomyocyte apoptosis. Moreover, the cardioprotective effect of METRNL overexpression was directly related to the activation of AMP-activated protein kinase (AMPK) and sirtuin1 (SIRT1). In summary, our data identified that METRNL may be a promising therapeutic target to mitigate pathological cardiac hypertrophy in the future.

Left atrial and ventricular deformation: alterations and predictive value of echocardiography parameters in end-stage renal disease patients after kidney transplantation

Abstract Aims End-stage renal disease (ESRD) patients are prone to alterations in cardiac haemodynamics specifically on the left ventricle (LV) and left atrial (LA) functions usually due to factors like uraemia, fluid overload, and inflammation. While studies on LV function in ESRD exist, research on LA function is limited. Successful kidney transplant (KTx) is believed to reverse pathological cardiac remodelling, and monitoring changes in cardiac strain before and after transplantation may guide pre- and post-transplant care. This study has two main objectives: to investigate alterations in LA and LV strain and other echocardiographic parameters after KTx and to identify independent factors predicting impaired strain parameters post-KTx. Methods and results We conducted a prospective cohort study of 49 ESRD patients who underwent KTx. Echocardiography was performed at baseline and at 3 months after KTx. LV end-diastolic volume, LV end-systolic volume, LV end-diastolic diameter, LV ejection fraction (LVEF), E/e′, maximum LA volume index (LAVi), LV global longitudinal strain (LVGLS), and all LA strain values, including booster (LASb), conduit (LAScd), and reservoir (LASr), improved significantly after KTx (P &amp;lt; 0.05). Regarding independent predictors of impaired LA and LV strains, pre-KTx values of LVEF, LAVi, and NT-proBNP were associated with LVGLS impairment after KTx; pre-KTx values of LAVi and LVEF were associated with LASr impairment after KTx. Conclusion The present study provided valuable evidence on the effects of KTx on uraemic cardiomyopathy demonstrated by LA strain and LV strain improvements and indicated pre-KTx LVEF and LAVi as significant independent predictors of LVGLS and LASr impairment after KTx.