Pubblicazioni recenti - cardiac fibrosis

• Alox15/15-HpETE Aggravates Myocardial Ischemia-Reperfusion Injury by Promoting Cardiomyocyte Ferroptosis.
  Circulation

  2023 Mar;():. doi: 10.1161/CIRCULATIONAHA.122.060257.
  
  Cai Wenbin, Liu Le, Shi Xuelian, Liu Yanan, Wang Jin, Fang Xuan, Chen Zhipeng, Ai Ding, Zhu Yi, Zhang Xu,
  
  Abstract
  
  BACKGROUND:
  Myocardial ischemia-reperfusion (I/R) injury causes cardiac dysfunction to myocardial cell loss and fibrosis. Prevention of cell death is important to protect cardiac function after I/R injury. The process of reperfusion can lead to multiple types of cardiomyocyte death, including necrosis, apoptosis, autophagy, and ferroptosis. However, the time point at which the various modes of cell death occur after reperfusion injury and the mechanisms underlying ferroptosis regulation in cardiomyocytes are still unclear.
  
  METHODS:
  Using a left anterior descending coronary artery ligation mouse model, we sought to investigate the time point at which the various modes of cell death occur after reperfusion injury. To discover the key molecules involved in cardiomyocyte ferroptosis, we performed a metabolomics study. Loss/gain-of-function approaches were used to understand the role of 15-lipoxygenase (Alox15) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (Pgc1?) in myocardial I/R injury.
  
  RESULTS:
  We found that apoptosis and necrosis occurred in the early phase of I/R injury, and that ferroptosis was the predominant form of cell death during the prolonged reperfusion. Metabolomic profiling of eicosanoids revealed that Alox15 metabolites accumulated in ferroptotic cardiomyocytes. We demonstrated that Alox15 expression was specifically increased in the injured area of the left ventricle below the suture and colocalized with cardiomyocytes. Furthermore, myocardial-specific knockout of Alox15 in mice alleviated I/R injury and restored cardiac function. 15-Hydroperoxyeicosatetraenoic acid (15-HpETE), an intermediate metabolite derived from arachidonic acid by Alox15, was identified as a trigger for cardiomyocyte ferroptosis. We explored the mechanism underlying its effects and found that 15-HpETE promoted the binding of Pgc1? to the ubiquitin ligase ring finger protein 34, leading to its ubiquitin-dependent degradation. Consequently, attenuated mitochondrial biogenesis and abnormal mitochondrial morphology were observed. ML351, a specific inhibitor of Alox15, increased the protein level of Pgc1?, inhibited cardiomyocyte ferroptosis, protected the injured myocardium, and caused cardiac function recovery.
  
  CONCLUSIONS:
  Together, our results established that Alox15/15-HpETE-mediated cardiomyocyte ferroptosis plays an important role in prolonged I/R injury.
  
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• Ultrasonic Microbubble Cavitation Deliver Gal-3 shRNA to Inhibit Myocardial Fibrosis after Myocardial Infarction.
  Pharmaceutics

  2023 Feb;15(3):. doi: 729.
  
  Li Wenqu, Jin Qiaofeng, Zhang Li, He Shukun, Song Yishu, Xu Lingling, Deng Cheng, Wang Lufang, Qin Xiaojuan, Xie Mingxing,
  
  Abstract
  
  Galectin-3 (Gal-3) participates in myocardial fibrosis (MF) in a variety of ways. Inhibiting the expression of Gal-3 can effectively interfere with MF. This study aimed to explore the value of Gal-3 short hairpin RNA (shRNA) transfection mediated by ultrasound-targeted microbubble destruction (UTMD) in anti-myocardial fibrosis and its mechanism. A rat model of myocardial infarction (MI) was established and randomly divided into control and Gal-3 shRNA/cationic microbubbles + ultrasound (Gal-3 shRNA/CMBs + US) groups. Echocardiography measured the left ventricular ejection fraction (LVEF) weekly, and the heart was harvested to analyze fibrosis, Gal-3, and collagen expression. LVEF in the Gal-3 shRNA/CMB + US group was improved compared with the control group. On day 21, the myocardial Gal-3 expression decreased in the Gal-3 shRNA/CMBs + US group. Furthermore, the proportion of the myocardial fibrosis area in the Gal-3 shRNA/CMBs + US group was 6.9 ± 0.41% lower than in the control group. After inhibition of Gal-3, there was a downregulation in collagen production (collagen I and III), and the ratio of Col I/Col III decreased. In conclusion, UTMD-mediated Gal-3 shRNA transfection can effectively silence the expression of Gal-3 in myocardial tissue, reduce myocardial fibrosis, and protect the cardiac ejection function.
  
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• Exposure to Doxorubicin Modulates the Cardiac Response to Isoproterenol in Male and Female Mice.
  Pharmaceuticals (Basel)

  2023 Mar;16(3):. doi: 391.
  
  Agostinucci Kevin, Grant Marianne K O, Melaku Wongel, Nair Chandini, Zordoky Beshay N,
  
  Abstract
  
  Sex is a salient risk factor in the development of doxorubicin-induced cardiotoxicity. Sex differences in the heart's ability to respond to hypertrophic stimuli in doxorubicin-exposed animals have not been reported. We identified the sexual dimorphic effects of isoproterenol in mice pre-exposed to doxorubicin. Male and female intact or gonadectomized C57BL/6N mice underwent five weekly intraperitoneal injections of 4 mg/kg doxorubicin followed by a five-week recovery period. Fourteen days of subcutaneous isoproterenol injections (10 mg/kg/day) were administered after the recovery period. Echocardiography was used to assess heart function one and five weeks after the last doxorubicin injection and on the fourteenth day of isoproterenol treatment. Thereafter, mice were euthanized, and the hearts were weighed and processed for histopathology and gene expression analysis. Doxorubicin did not produce overt cardiac dysfunction in male or female mice before starting isoproterenol treatment. The chronotropic response to a single isoproterenol injection was blunted by doxorubicin, but the inotropic response was maintained in both males and females. Pre-exposure to doxorubicin caused cardiac atrophy in both control and isoproterenol-treated male mice but not in female mice. Counterintuitively, pre-exposure to doxorubicin abrogated isoproterenol-induced cardiac fibrosis. However, there were no sex differences in the expression of markers of pathological hypertrophy, fibrosis, or inflammation. Gonadectomy did not reverse the sexually dimorphic effects of doxorubicin. Additionally, pre-exposure to doxorubicin abrogated the hypertrophic response to isoproterenol in castrated male mice but not in ovariectomized female mice. Therefore, pre-exposure to doxorubicin caused male-specific cardiac atrophy that persisted after isoproterenol treatment, which could not be prevented by gonadectomy.
  
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• Effect of Selenium Nanoparticles and/or Bee Venom against STZ-Induced Diabetic Cardiomyopathy and Nephropathy.
  Metabolites

  2023 Mar;13(3):. doi: 400.
  
  Lotfy Mona M, Dowidar Mohamed F, Ali Haytham A, Ghonimi Wael A M, Al-Farga Ammar, Ahmed Amany I,
  
  Abstract
  
  The main purpose of our study was to examine the role of selenium nanoparticles (SeNPs) and/or bee venom (BV) in ameliorating diabetic cardiomyopathy (DCM) and nephropathy (DN) at the biochemical, histopathological and molecular levels. Fifty male albino rats were used in this experiment, divided into five groups: control, Streptozocin (STZ) diabetic, STZ-diabetic treated with SeNPs, STZ-diabetic treated with BV, and STZ-diabetic treated with SeNPs and BV. Biochemically, STZ injection resulted in a significant increase in serum glucose, BUN, creatinine, CRP, CK-MB, AST, LDH and cardiac troponins with a significant decrease in the serum insulin and albumin concentrations. Histopathologically, STZ injection resulted in diabetes, as revealed by glomerulonephritis, perivascular hemorrhage, inflammatory cell infiltrations and fibrosis, with widening of interstitial spaces of cardiomyocytes, loss of muscle cells continuity and some hyaline degeneration. At the molecular levels, the expression levels of miRNA 328, miRNA-21, TGF?1, TGF?1R, JAK1, STST-3, SMAD-1 and NF?? genes were significantly up-regulated, whereas the expression levels of SMAD-7 were significantly down-regulated. It is concluded that SeNPs and/or BV administration ameliorates the deleterious effects resulting from STZ administration through improving the biochemical, histopathological and molecular effects, suggesting their protective role against the long-term diabetic complications of DCM and DN.
  
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• Potential Prognostic Value of Native T1 in Pulmonary Hypertension Patients.
  Life (Basel)

  2023 Mar;13(3):. doi: 775.
  
  Cerne John W, Shehata Christina, Ragin Ann, Pathrose Ashitha, Veer Manik, Subedi Kamal, Allen Bradley D, Avery Ryan J, Markl Michael, Carr James C,
  
  Abstract
  
  Native T1, extracellular volume fraction (ECV), and late gadolinium enhancement (LGE) characterize myocardial tissue and relate to patient prognosis in a variety of diseases, including pulmonary hypertension. The purpose of this study was to evaluate if left ventricle (LV) fibrosis measurements have prognostic value for cardiac outcomes in pulmonary hypertension subgroups. 54 patients with suspected pulmonary hypertension underwent right-heart catheterization and were classified into pulmonary hypertension subgroups: pre-capillary component (PreCompPH) and isolated post-capillary (IpcPH). Cardiac magnetic resonance imaging (MRI) scans were performed with the acquisition of balanced cine steady-state free precession, native T1, and LGE pulse sequences to measure cardiac volumes and myocardial fibrosis. Associations between cardiac events and cardiac MRI measurements were analyzed within PreCompPH and IpcPH patients. IpcPH: LV native T1 was higher in patients who experienced a cardiac event within two years vs. those who did not. In patients with LV native T1 > 1050 ms, the rate of cardiac events was higher. ECV and quantitative LGE did not differ between groups. PreCompPH: native T1, ECV, and quantitative/qualitative LGE did not differ between patients who experienced a cardiac event within two years vs. those who did not. LV native T1 may have potential value for forecasting cardiac events in IpcPH, but not in PreCompPH, patients.
  
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• The Use of Multimodality Imaging for the Diagnosis of Myocardial Outpouchings and Invaginations: A Systematic Review.
  Life (Basel)

  2023 Feb;13(3):. doi: 650.
  
  Pavasini Rita, Bianchi Nicola, Frascaro Federica, Marchini Federico, Meossi Sofia, Zanarelli Luca, Sanguettoli Federico, Cossu Alberto, Tonet Elisabetta, Passarini Giulia, Campo Gianluca,
  
  Abstract
  
  Cardiac ventricular outpouchings and invaginations are rare structural abnormalities and usually incidental findings during cardiac imaging. A definitive diagnosis is possible through the use of multimodality imaging. A systematic review of the literature was carried out in November 2022 to identify studies regarding ventricular outpouchings and invaginations. The main aim of the review is to summarize knowledge regarding epidemiology, etiology, diagnosis and prognosis of patients with ventricular outpouchings (aneurisms or diverticula) and invaginations (crypts and recesses). Overall, 26 studies published between 2000 and 2020 were included in the review. Diverticula and congenital aneurysms incidence ranges between 0.6 and 4.1%. Myocardial recesses and crypts range between 9% in the general population and up to 25% in patients with hypertrophic cardiomyopathy. The combined use of echocardiography, cardiac computed tomography (CCT) and cardiac magnetic resonance (CMR) is useful to establish tissue contractility, fibrosis, extension and relationship with adjacent structures for differential diagnosis of both invaginations and outpouchings. In conclusion, both outpouchings and invaginations are rare entities: a definitive diagnosis may be aided by the use of combining multiple imaging techniques, and the treatment depends both on the lesion-specific risk of complications and on the potential association of some lesions with cardiomyopathy.
  
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• Cryoballoon-Induced Circumferential Pulmonary Vein Fibrosis, Assessed by Late Gadolinium-Enhancement Cardiac Magnetic Resonance Imaging, and Its Correlation with Clinical Atrial Fibrillation Recurrence.
  J Clin Med

  2023 Mar;12(6):. doi: 2442.
  
  Rav Acha Moshe, Tovia-Brodie Oholi, Michowitz Yoav, Bayya Feras, Shaheen Fauzi F, Abuhatzera Shalom, Medina Aharon, Glikson Michael, Wolak Arik,
  
  Abstract
  
  BACKGROUND:
  Prior studies evaluating post-atrial fibrillation (AF) ablation pulmonary vein (PV) ostial gaps via magnetic resonance imaging (MRI) have shown circumferential PV fibrosis in a minority of patients, and their correlation with AF recurrence was weak. These studies were mostly based on radio-frequency AF ablations.
  
  AIM:
  We aimed to assess cryoballoon ablation-induced PV fibrosis via MRI and its correlation with AF recurrence.
  
  METHODS AND RESULTS:
  This was a prospective study of consecutive patients with symptomatic AF who underwent pre- and post-ablation MRI to assess baseline and ablation-induced fibrosis, respectively. Post-ablation PV gaps were assessed by new semi-quantitative visual analysis assisted by computerized ADAS analysis. AF recurrence monitored via multiple ECGs and event monitoring at 6 and 12 months post ablation. Nineteen patients with 80 PVs were included, age 56 ± 11, with paroxysmal and persistent AF in 17/19 and 2/19 patients, respectively. Baseline MRI showed minimal LA fibrosis. All patients underwent successful cryoballoon PV electrical isolation. Post-ablation MRI revealed circumferential PV fibrosis among 63/80 (78.8%) PVs and partial fibrosis with major gaps among 17/80 (21.2%) PVs. AF recurred within one year in 5/9 (55.5%) patients with partial PV fibrosis, while no AF recurred among the 10 patients in whom all PVs had circumferential fibrosis (
  CONCLUSION:
  Cryoballoon AF ablation results in circumferential PV fibrosis in the majority of PVs, as assessed by a new clinically relevant MRI-LGE analysis. Significant correlation was found between major PV gaps on post-ablation MRI and AF recurrence, suggesting that MRI might have the ability to predict AF recurrence.
  
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• Ion Channels in the Development and Remodeling of the Aortic Valve.
  Int J Mol Sci

  2023 Mar;24(6):. doi: 5860.
  
  Simard Christophe, Aize Margaux, Chaigne Sébastien, Mpweme Bangando Harlyne, Guinamard Romain,
  
  Abstract
  
  The role of ion channels is extensively described in the context of the electrical activity of excitable cells and in excitation-contraction coupling. They are, through this phenomenon, a key element for cardiac activity and its dysfunction. They also participate in cardiac morphological remodeling, in particular in situations of hypertrophy. Alongside this, a new field of exploration concerns the role of ion channels in valve development and remodeling. Cardiac valves are important components in the coordinated functioning of the heart by ensuring unidirectional circulation essential to the good efficiency of the cardiac pump. In this review, we will focus on the ion channels involved in both the development and/or the pathological remodeling of the aortic valve. Regarding valve development, mutations in genes encoding for several ion channels have been observed in patients suffering from malformation, including the bicuspid aortic valve. Ion channels were also reported to be involved in the morphological remodeling of the valve, characterized by the development of fibrosis and calcification of the leaflets leading to aortic stenosis. The final stage of aortic stenosis requires, until now, the replacement of the valve. Thus, understanding the role of ion channels in the progression of aortic stenosis is an essential step in designing new therapeutic approaches in order to avoid valve replacement.
  
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• Autoantibodies against PIP4K2B and AKT3 Are Associated with Skin and Lung Fibrosis in Patients with Systemic Sclerosis.
  Int J Mol Sci

  2023 Mar;24(6):. doi: 5629.
  
  Geroldinger-Simi? Marija, Bayati Shaghayegh, Pohjanen Emmie, Sepp Norbert, Nilsson Peter, Pin Elisa,
  
  Abstract
  
  Systemic sclerosis (SSc) is a rare autoimmune systemic disease that leads to decreased survival and quality of life due to fibrosis, inflammation, and vascular damage in the skin and/or vital organs. Early diagnosis is crucial for clinical benefit in SSc patients. Our study aimed to identify autoantibodies in the plasma of SSc patients that are associated with fibrosis in SSc. Initially, we performed a proteome-wide screening on sample pools from SSc patients by untargeted autoantibody screening on a planar antigen array (including 42,000 antigens representing 18,000 unique proteins). The selection was complemented with proteins reported in the literature in the context of SSc. A targeted antigen bead array was then generated with protein fragments representing the selected proteins and used to screen 55 SSc plasma samples and 52 matched controls. We found eleven autoantibodies with a higher prevalence in SSc patients than in controls, eight of which bound to proteins associated with fibrosis. Combining these autoantibodies in a panel could lead to the subgrouping of SSc patients with fibrosis. Anti-Phosphatidylinositol-5-phosphate 4-kinase type 2 beta (PIP4K2B)- and anti-AKT Serine/Threonine Kinase 3 (AKT3)-antibodies should be further explored to confirm their association with skin and lung fibrosis in SSc patients.
  
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• Cardiac Functional and Structural Abnormalities in a Mouse Model of CDKL5 Deficiency Disorder.
  Int J Mol Sci

  2023 Mar;24(6):. doi: 5552.
  
  Loi Manuela, Bastianini Stefano, Candini Giulia, Rizzardi Nicola, Medici Giorgio, Papa Valentina, Gennaccaro Laura, Mottolese Nicola, Tassinari Marianna, Uguagliati Beatrice, Berteotti Chiara, Martire Viviana Lo, Zoccoli Giovanna, Cenacchi Giovanna, Trazzi Stefania, Bergamini Christian, Ciani Elisabetta,
  
  Abstract
  
  CDKL5 (cyclin-dependent kinase-like 5) deficiency disorder (CDD) is a severe neurodevelopmental disease that mostly affects girls, who are heterozygous for mutations in the X-linked gene. Mutations in the gene lead to a lack of CDKL5 protein expression or function and cause numerous clinical features, including early-onset seizures, marked hypotonia, autistic features, gastrointestinal problems, and severe neurodevelopmental impairment. Mouse models of CDD recapitulate several aspects of CDD symptomology, including cognitive impairments, motor deficits, and autistic-like features, and have been useful to dissect the role of CDKL5 in brain development and function. However, our current knowledge of the function of CDKL5 in other organs/tissues besides the brain is still quite limited, reducing the possibility of broad-spectrum interventions. Here, for the first time, we report the presence of cardiac function/structure alterations in heterozygous +/- female mice. We found a prolonged QT interval (corrected for the heart rate, QTc) and increased heart rate in +/- mice. These changes correlate with a marked decrease in parasympathetic activity to the heart and in the expression of the and voltage-gated channels. Interestingly, +/- hearts showed increased fibrosis, altered gap junction organization and connexin-43 expression, mitochondrial dysfunction, and increased ROS production. Together, these findings not only contribute to our understanding of the role of CDKL5 in heart structure/function but also document a novel preclinical phenotype for future therapeutic investigation.
  
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• An Adjuvant Stem Cell Patch with Coronary Artery Bypass Graft Surgery Improves Diastolic Recovery in Porcine Hibernating Myocardium.
  Int J Mol Sci

  2023 Mar;24(6):. doi: 5475.
  
  Aggarwal Rishav, Potel Koray N, Shao Annie, So Simon W, Swingen Cory, Reyes Christina P, Rose Rebecca, Wright Christin, Hocum Stone Laura L, McFalls Edward O, Butterick Tammy A, Kelly Rosemary F,
  
  Abstract
  
  Diastolic dysfunction persists despite coronary artery bypass graft surgery (CABG) in patients with hibernating myocardium (HIB). We studied whether the adjunctive use of a mesenchymal stem cells (MSCs) patch during CABG improves diastolic function by reducing inflammation and fibrosis. HIB was induced in juvenile swine by placing a constrictor on the left anterior descending (LAD) artery, causing myocardial ischemia without infarction. At 12 weeks, CABG was performed using the left-internal-mammary-artery (LIMA)-to-LAD graft with or without placement of an epicardial vicryl patch embedded with MSCs, followed by four weeks of recovery. The animals underwent cardiac magnetic resonance imaging (MRI) prior to sacrifice, and tissue from septal and LAD regions were collected to assess for fibrosis and analyze mitochondrial and nuclear isolates. During low-dose dobutamine infusion, diastolic function was significantly reduced in HIB compared to the control, with significant improvement after CABG + MSC treatment. In HIB, we observed increased inflammation and fibrosis without transmural scarring, along with decreased peroxisome proliferator-activated receptor-gamma coactivator (PGC1?), which could be a possible mechanism underlying diastolic dysfunction. Improvement in PGC1? and diastolic function was noted with revascularization and MSCs, along with decreased inflammatory signaling and fibrosis. These findings suggest that adjuvant cell-based therapy during CABG may recover diastolic function by reducing oxidant stress-inflammatory signaling and myofibroblast presence in the myocardial tissue.
  
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• Lifetime Evaluation of Left Ventricular Structure and Function in Male C57BL/6J Mice after Gamma and Space-Type Radiation Exposure.
  Int J Mol Sci

  2023 Mar;24(6):. doi: 5451.
  
  Brojakowska Agnieszka, Jackson Cedric J, Bisserier Malik, Khlgatian Mary K, Grano Cynthia, Blattnig Steve R, Zhang Shihong, Fish Kenneth M, Chepurko Vadim, Chepurko Elena, Gillespie Virginia, Dai Ying, Lee Brooke, Garikipati Venkata Naga Srikanth, Hadri Lahouaria, Kishore Raj, Goukassian David A,
  
  Abstract
  
  The lifetime effects of space irradiation (IR) on left ventricular (LV) function are unknown. The cardiac effects induced by space-type IR, specifically 5-ion simplified galactic cosmic ray simulation (simGCRsim), are yet to be discovered. Three-month-old, age-matched, male C57BL/6J mice were irradiated with Cs gamma (?; 100, 200 cGy) and simGCRsim (50 and 100 cGy). LV function was assessed via transthoracic echocardiography at 14 and 28 days (early), and at 365, 440, and 660 (late) days post IR. We measured the endothelial function marker brain natriuretic peptide in plasma at three late timepoints. We assessed the mRNA expression of the genes involved in cardiac remodeling, fibrosis, inflammation, and calcium handling in LVs harvested at 660 days post IR. All IR groups had impaired global LV systolic function at 14, 28, and 365 days. At 660 days, 50 cGy simGCRsim-IR mice exhibited preserved LV systolic function with altered LV size and mass. At this timepoint, the simGCRsim-IR mice had elevated levels of cardiac fibrosis, inflammation, and hypertrophy markers , , , and , suggesting that space-type IR may induce the cardiac remodeling processes that are commonly associated with diastolic dysfunction. IR groups showing statistical significance were modeled to calculate the Relative Biological Effectiveness (RBE) and Radiation Effects Ratio (RER). The observed dose-response shape did not indicate a lower threshold at these IR doses. A single full-body IR at doses of 100-200 cGy for ?-IR, and 50-100 cGy for simGCRsim-IR decreases the global LV systolic function in WT mice as early as 14 and 28 days after exposure, and at 660 days post IR. Interestingly, there is an intermediate time point (365 days) where the impairment in LV function is observed. These findings do not exclude the possibility of increased acute or degenerative cardiovascular disease risks at lower doses of space-type IR, and/or when combined with other space travel-associated stressors such as microgravity.
  
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• miRNAs in Uremic Cardiomyopathy: A Comprehensive Review.
  Int J Mol Sci

  2023 Mar;24(6):. doi: 5425.
  
  D'Agostino Mario, Mauro Davide, Zicarelli Mariateresa, Carullo Nazareno, Greco Marta, Andreucci Michele, Coppolino Giuseppe, Bolignano Davide,
  
  Abstract
  
  Uremic Cardiomyopathy (UCM) is an irreversible cardiovascular complication that is highly pervasive among chronic kidney disease (CKD) patients, particularly in End-Stage Kidney Disease (ESKD) individuals undergoing chronic dialysis. Features of UCM are an abnormal myocardial fibrosis, an asymmetric ventricular hypertrophy with subsequent diastolic dysfunction and a complex and multifactorial pathogenesis where underlying biological mechanisms remain partly undefined. In this paper, we reviewed the key evidence available on the biological and clinical significance of micro-RNAs (miRNAs) in UCM. miRNAs are short, noncoding RNA molecules with regulatory functions that play a pivotal role in myriad basic cellular processes, such as cell growth and differentiation. Deranged miRNAs expression has already been observed in various diseases, and their capacity to modulate cardiac remodeling and fibrosis under either physiological or pathological conditions is well acknowledged. In the context of UCM, robust experimental evidence confirms a close involvement of some miRNAs in the key pathways that are known to trigger or worsen ventricular hypertrophy or fibrosis. Moreover, very preliminary findings may set the stage for therapeutic interventions targeting specific miRNAs for ameliorating heart damage. Finally, scant but promising clinical evidence may suggest a potential future application of circulating miRNAs as diagnostic or prognostic biomarkers for improving risk stratification in UCM as well.
  
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• PPAR Alpha Activation by Clofibrate Alleviates Ischemia/Reperfusion Injury in Metabolic Syndrome Rats by Decreasing Cardiac Inflammation and Remodeling and by Regulating the Atrial Natriuretic Peptide Compensatory Response.
  Int J Mol Sci

  2023 Mar;24(6):. doi: 5321.
  
  Sánchez-Aguilar María, Ibarra-Lara Luz, Cano-Martínez Agustina, Soria-Castro Elizabeth, Castrejón-Téllez Vicente, Pavón Natalia, Osorio-Yáñez Citlalli, Díaz-Díaz Eulises, Rubio-Ruíz María Esther,
  
  Abstract
  
  Metabolic syndrome (MetS) is a cluster of factors that increase the risk of developing diabetes, stroke, and heart failure. The pathophysiology of injury by ischemia/reperfusion (I/R) is highly complex and the inflammatory condition plays an important role by increasing matrix remodeling and cardiac apoptosis. Natriuretic peptides (NPs) are cardiac hormones with numerous beneficial effects mainly mediated by a cell surface receptor named atrial natriuretic peptide receptor (ANPr). Although NPs are powerful clinical markers of cardiac failure, their role in I/R is still controversial. Peroxisome proliferator-activated receptor ? agonists exert cardiovascular therapeutic actions; however, their effect on the NPs' signaling pathway has not been extensively studied. Our study provides important insight into the regulation of both ANP and ANPr in the hearts of MetS rats and their association with the inflammatory conditions caused by damage from I/R. Moreover, we show that pre-treatment with clofibrate was able to decrease the inflammatory response that, in turn, decreases myocardial fibrosis, the expression of metalloprotease 2 and apoptosis. Treatment with clofibrate is also associated with a decrease in ANP and ANPr expression.
  
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• microRNAs as Biomarkers of Endothelial Dysfunction and Therapeutic Target in the Pathogenesis of Atrial Fibrillation.
  Int J Mol Sci

  2023 Mar;24(6):. doi: 5307.
  
  Desantis Vanessa, Potenza Maria Assunta, Sgarra Luca, Nacci Carmela, Scaringella Antonietta, Cicco Sebastiano, Solimando Antonio Giovanni, Vacca Angelo, Montagnani Monica,
  
  Abstract
  
  The pathophysiology of atrial fibrillation (AF) may involve atrial fibrosis/remodeling and dysfunctional endothelial activities. Despite the currently available treatment approaches, the progression of AF, its recurrence rate, and the high mortality risk of related complications underlay the need for more advanced prognostic and therapeutic strategies. There is increasing attention on the molecular mechanisms controlling AF onset and progression points to the complex cell to cell interplay that triggers fibroblasts, immune cells and myofibroblasts, enhancing atrial fibrosis. In this scenario, endothelial cell dysfunction (ED) might play an unexpected but significant role. microRNAs (miRNAs) regulate gene expression at the post-transcriptional level. In the cardiovascular compartment, both free circulating and exosomal miRNAs entail the control of plaque formation, lipid metabolism, inflammation and angiogenesis, cardiomyocyte growth and contractility, and even the maintenance of cardiac rhythm. Abnormal miRNAs levels may indicate the activation state of circulating cells, and thus represent a specific read-out of cardiac tissue changes. Although several unresolved questions still limit their clinical use, the ease of accessibility in biofluids and their prognostic and diagnostic properties make them novel and attractive biomarker candidates in AF. This article summarizes the most recent features of AF associated with miRNAs and relates them to potentially underlying mechanisms.
  
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• Role of Klotho and AGE/RAGE-Wnt/?-Catenin Signalling Pathway on the Development of Cardiac and Renal Fibrosis in Diabetes.
  Int J Mol Sci

  2023 Mar;24(6):. doi: 5241.
  
  Martín-Carro Beatriz, Martín-Vírgala Julia, Fernández-Villabrille Sara, Fernández-Fernández Alejandra, Pérez-Basterrechea Marcos, Navarro-González Juan F, Donate-Correa Javier, Mora-Fernández Carmen, Dusso Adriana S, Carrillo-López Natalia, Panizo Sara, Naves-Díaz Manuel, Fernández-Martín José L, Cannata-Andía Jorge B, Alonso-Montes Cristina,
  
  Abstract
  
  Fibrosis plays an important role in the pathogenesis of long-term diabetic complications and contributes to the development of cardiac and renal dysfunction. The aim of this experimental study, performed in a long-term rat model, which resembles type 1 diabetes mellitus, was to investigate the role of soluble Klotho (sKlotho), advanced glycation end products (AGEs)/receptor for AGEs (RAGE), fibrotic Wnt/?-catenin pathway, and pro-fibrotic pathways in kidney and heart. Diabetes was induced by streptozotocin. Glycaemia was maintained by insulin administration for 24 weeks. Serum and urine sKlotho, AGEs, soluble RAGE (sRAGE) and biochemical markers were studied. The levels of Klotho, RAGEs, ADAM10, markers of fibrosis (collagen deposition, fibronectin, TGF-?1, and Wnt/?-catenin pathway), hypertrophy of the kidney and/or heart were analysed. At the end of study, diabetic rats showed higher levels of urinary sKlotho, AGEs and sRAGE and lower serum sKlotho compared with controls without differences in the renal Klotho expression. A significant positive correlation was found between urinary sKlotho and AGEs and urinary albumin/creatinine ratio (uACR). Fibrosis and RAGE levels were significantly higher in the heart without differences in the kidney of diabetic rats compared to controls. The results also suggest the increase in sKlotho and sRAGE excretion may be due to polyuria in the diabetic rats.
  
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• Identification of Two Homozygous Variants in and Genes Associated with Severe Infantile Cardiomyopathy.
  Genes (Basel)

  2023 Mar;14(3):. doi: 659.
  
  Szulik Marta W, Reyes-Múgica Miguel, Marker Daniel F, Gomez Ana M, Zinn Matthew D, Walsh Leslie K, Ochoa Juan Pablo, Franklin Sarah, Ghaloul-Gonzalez Lina,
  
  Abstract
  
  Mutations in cardiac genes are one of the primary causes of infantile cardiomyopathy. In this study, we report the genetic findings of two siblings carrying variations in the and genes. The first patient is a female proband exhibiting hypertrophic cardiomyopathy (HCM) and biventricular heart failure carrying a truncating homozygous variant c.1224-52G>A (IVS13-52G>A) and a novel homozygous variant (c.302A>G; p.Asn101Ser) in the gene. The second patient, the proband's sibling, is a male infant diagnosed with hypertrophic cardiomyopathy and carries the same homozygous variant. While this specific variant (c.1224-52G>A, IVS13-52G>A) has been previously reported to be associated with adult-onset hypertrophic cardiomyopathy, this is the first report linking it to infantile cardiomyopathy. In addition, this work describes, for the first time, a novel variant (c.302A>G; p.Asn101Ser) that has never been reported. We performed a histopathological evaluation of tissues collected from both probands and show that these variants lead to myofibrillar disarray, reduced and irregular mitochondrial cristae and cardiac fibrosis. Together, these results provide critical insight into the molecular functionality of these genes in human cardiac physiology.
  
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• TNC Accelerates Hypoxia-Induced Cardiac Injury in a METTL3-Dependent Manner.
  Genes (Basel)

  2023 Feb;14(3):. doi: 591.
  
  Cheng Hao, Li Linnan, Xue Junqiang, Ma Jianying, Ge Junbo,
  
  Abstract
  
  Cardiac fibrosis and cardiomyocyte apoptosis are reparative processes after myocardial infarction (MI), which results in cardiac remodeling and heart failure at last. Tenascin-C (TNC) consists of four distinct domains, which is a large multimodular glycoprotein of the extracellular matrix. It is also a key regulator of proliferation and apoptosis in cardiomyocytes. As a significant mA regulator, METTL3 binds mA sites in mRNA to control its degradation, maturation, stabilization, and translation. Whether METTL3 regulates the occurrence and development of myocardial infarction through the mA modification of TNC mRNA deserves our study. Here, we have demonstrated that overexpression of METTL3 aggravated cardiac dysfunction and cardiac fibrosis after 4 weeks after MI. Moreover, we also demonstrated that TNC resulted in cardiac fibrosis and cardiomyocyte apoptosis after MI. Mechanistically, METTL3 led to enhanced mA levels of TNC mRNA and promoted TNC mRNA stability. Then, we mutated one mA site "A" to "T", and the binding ability of METTL3 was reduced. In conclusion, METTL3 is involved in cardiac fibrosis and cardiomyocyte apoptosis by increasing mA levels of TNC mRNA and may be a promising target for the therapy of cardiac fibrosis after MI.
  
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• Leucine-Rich Alpha-2-Glycoprotein: A Novel Predictor of Diastolic Dysfunction.
  Biomedicines

  2023 Mar;11(3):. doi: 944.
  
  Loch Alexander, Tan Kok Leng, Danaee Mahmoud, Idris Iskandar, Ng Mei Li,
  
  Abstract
  
  Leucine-rich ?2-glycoprotein (LRG1) mediates cardiac fibrocyte activation. It is upregulated in inflammatory conditions, atherosclerosis, and fibrosis. Diastolic dysfunction (DD) is due to myocardial fibrosis. This cross-sectional study examined the relationship between LRG1 and DD. Patients with symptoms of chronic coronary ischemia were recruited. Patients with symptoms of overt heart failure, ejection fraction (EF)
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• Novel Oxidative Stress Biomarkers with Risk Prognosis Values in Heart Failure.
  Biomedicines

  2023 Mar;11(3):. doi: 917.
  
  Ng Mei Li, Ang Xu, Yap Kwan Yi, Ng Jun Jie, Goh Eugene Chen Howe, Khoo Benjamin Bing Jie, Richards Arthur Mark, Drum Chester Lee,
  
  Abstract
  
  Oxidative stress (OS) is mediated by reactive oxygen species (ROS), which in cardiovascular and other disease states, damage DNA, lipids, proteins, other cellular and extra-cellular components. OS is both initiated by, and triggers inflammation, cardiomyocyte apoptosis, matrix remodeling, myocardial fibrosis, and neurohumoral activation. These have been linked to the development of heart failure (HF). Circulating biomarkers generated by OS offer potential utility in patient management and therapeutic targeting. Novel OS-related biomarkers such as NADPH oxidases (sNox2-dp, Nrf2), advanced glycation end-products (AGE), and myeloperoxidase (MPO), are signaling molecules reflecting pathobiological changes in HF. This review aims to evaluate current OS-related biomarkers and their associations with clinical outcomes and to highlight those with greatest promise in diagnosis, risk stratification and therapeutic targeting in HF.
  
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