Vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs) frequently induce cardiovascular adverse events, though VEGFR-TKIs contribute to the improvement of the prognosis ...of patients with malignancies. It is widely accepted that VEGFR-TKIs impair left ventricular systolic functions; however, their effects on diastolic functions remain to be fully elucidated. The purpose of this study was to analyze the impact of VEGFR-TKIs on left ventricular diastolic functions. This study was designed as a retrospective single-center cohort study in Japan. We assessed 24 cases who received VEGFR-TKI monotherapy (sunitinib, sorafenib, pazopanib, axitinib) with left ventricular ejection fraction (LVEF) above 50% during the therapy at the Osaka University Hospital from January 2008 to June 2019. Left ventricular diastolic functions were evaluated by the change in echocardiographic parameters before and after the VEGFR-TKI treatment. Both septal e' and lateral e's decreased after treatment (septal e': before, 6.1 ± 1.8; after, 5.0 ± 1.9; n = 21, P < 0.01; lateral e': before, 8.7 ± 2.8; after, 6.9 ± 2.3; n = 21, P < 0.01). E/A declined after VEGFR-TKIs administration, though not statistically significantly. In 20 cases with at least one risk factor for heart failure with preserved ejection fraction (HFpEF), E/A significantly decreased (0.87 ± 0.34 versus 0.68 ± 0.14; P < 0.05) as well as the septal and lateral e's. These results suggest that treatment with VEGFR-TKIs impairs left ventricular diastolic functions in patients with preserved LVEF, especially in those with risk factors for HFpEF.
The Japanese national guidelines recommend significantly lower doses of carvedilol for heart failure with reduced ejection fraction (HFrEF) management than the US guidelines. Using real-world data, ...we determined whether initial and target doses of carvedilol in Japanese patients (JPNs) differ from those in US patients (USPs), especially in Asian Americans (ASA) and Caucasians (CA), and investigated differences in outcomes. We collected data from the electronic medical records, including demographics, carvedilol dosing, tolerability, cardiac functional indicators like EF, cardiovascular events including all-cause deaths, and laboratory values from the University of California, San Diego Health and Osaka University. JPNs had significantly lower doses (mg/day) of carvedilol initiation (66 USPs composed of 38 CAs and 28 ASAs, 17.1±16.2; 93 JPNs, 4.3±4.2, p<0.001) and one year after initiation (33.0±21.8; 11.2±6.5, p<0.001), and a significantly lower relative rate (RR) of dose discontinuation and reduction than USPs (RR: 0.406, 95% confidence interval (CI): 0.181-0.911, p<0.05). CAs showed the highest reduction rate (0.184), and ASAs had the highest discontinuation rate (0.107). A slight mean difference with narrow 95% CI ranges straddling zero was observed between the two regions in the change from the baseline of each cardiac functional indicator (LVEF, -0.68 -5.49-4.12; LVDd, -0.55 -3.24-2.15; LVDd index, -0.25 -1.92-1.43; LVDs, -0.03 -3.84-3.90; LVDs index, -0.04 -2.38-2.30; heart rate, 1.62 -3.07-6.32). The event-free survival showed no difference (p = 0.172) among the races. Conclusively, despite JPNs exhibiting markedly lower carvedilol doses, their dose effectiveness has the potential to be non-inferior to that in USPs. Dose de-escalation, not discontinuation, could be an option in some Asian and ASA HFrEF patients intolerable to high doses of carvedilol.
Because mammalian cardiomyocytes largely cease to proliferate immediately after birth, the regenerative activity of the heart is limited. To date, much effort has been made to clarify the regulatory ...mechanism of cardiomyocyte proliferation because the amplification of cardiomyocytes could be a promising strategy for heart regenerative therapy. Recently, it was reported that the inhibition of glycogen synthase kinase (GSK)‐3 promotes the proliferation of neonatal rat cardiomyocytes (NRCMs) and human iPS cell‐derived cardiomyocytes (hiPSC‐CMs). Additionally, Yes‐associated protein (YAP) induces cardiomyocyte proliferation. The purpose of this study was to address the importance of YAP activity in cardiomyocyte proliferation induced by GSK‐3 inhibitors (GSK‐3Is) to develop a novel strategy for cardiomyocyte amplification. Immunofluorescent microscopic analysis using an anti‐Ki‐67 antibody demonstrated that the treatment of NRCMs with GSK‐3Is, such as BIO and CHIR99021, increased the ratio of proliferative cardiomyocytes. YAP was localized in the nuclei of more than 95% of cardiomyocytes, either in the presence or absence of GSK‐3Is, indicating that YAP was endogenously activated. GSK‐3Is increased the expression of β‐catenin and promoted its translocation into the nucleus without influencing YAP activity. The knockdown of YAP using siRNA or pharmacological inhibition of YAP using verteporfin or CIL56 dramatically reduced GSK‐3I‐induced cardiomyocyte proliferation without suppressing β‐catenin activation. Interestingly, the inhibition of GSK‐3 also induced the proliferation of hiPSC‐CMs under sparse culture conditions, where YAP was constitutively activated. In contrast, under dense culture conditions, in which YAP activity was suppressed, the proliferative effects of GSK‐3Is on hiPSC‐CMs were not detected. Importantly, the activation of YAP by the knockdown of α‐catenin restored the proproliferative activity of GSK‐3Is. Collectively, YAP activation potentiates the GSK‐3I‐induced proliferation of cardiomyocytes. The blockade of GSK‐3 in combination with YAP activation resulted in remarkable amplification of cardiomyocytes.
GSK‐3 inhibitors (GSK‐3Is) induce cardiomyocyte proliferation via β‐catenin. The activation of YAP potentiates GSK‐3I‐induced proliferation without modulating β‐catenin signaling. The blockade of GSK‐3 in combination with YAP activation could be a promising strategy for the amplification of cardiomyocytes.
Prevention of kidney fibrosis is an essential requisite for effective therapy in preventing chronic kidney disease (CKD). Here, we identify Old astrocyte specifically induced substance (OASIS)/cAMP ...responsive element‐binding protein 3‐like 1 (CREB3l1), a CREB/ATF family transcription factor, as a candidate profibrotic gene that drives the final common pathological step along the fibrotic pathway in CKD. Although microarray data from diseased patient kidneys and fibrotic mouse model kidneys both exhibit OASIS/Creb3l1 upregulation, the pathophysiological roles of OASIS in CKD remains unknown. Immunohistochemistry revealed that OASIS protein was overexpressed in human fibrotic kidney compared with normal kidney. Moreover, OASIS was upregulated in murine fibrotic kidneys, following unilateral ureteral obstruction (UUO), resulting in an increase in the number of OASIS‐expressing pathological myofibroblasts. In vitro assays revealed exogenous TGF‐β1 increased OASIS expression coincident with fibroblast‐to‐myofibroblast transition and OASIS contributed to TGF‐β1–mediated myofibroblast migration and increased proliferation. Significantly, in vivo kidney fibrosis induced via UUO or ischemia/reperfusion injury was ameliorated by systemic genetic knockout of OASIS, accompanied by reduced myofibroblast proliferation. Microarrays revealed that the transmembrane glycoprotein Bone marrow stromal antigen 2 (Bst2) expression was reduced in OASIS knockout myofibroblasts. Interestingly, a systemic anti‐Bst2 blocking antibody approach attenuated kidney fibrosis in normal mice but not in OASIS knockout mice after UUO, signifying Bst2 functions downstream of OASIS. Finally, myofibroblast‐restricted OASIS conditional knockouts resulted in resistance to kidney fibrosis. Taken together, OASIS in myofibroblasts promotes kidney fibrosis, at least in part, via increased Bst2 expression. Thus, we have identified and demonstrated that OASIS signaling is a novel regulator of kidney fibrosis.
Glycoprotein 130 is the common receptor subunit for the interleukin (IL)-6 cytokine family. Previously, we reported that pretreatment of IL-11, an IL-6 family cytokine, activates the glycoprotein 130 ...signaling pathway in cardiomyocytes and prevents ischemia/reperfusion injury in vivo; however, its long-term effects on cardiac remodeling after myocardial infarction (MI) remain to be elucidated.
MI was generated by ligating the left coronary artery in C57BL/6 mice. Real-time reverse transcription polymerase chain reaction analyses showed that IL-11 mRNA was remarkably upregulated in the hearts exposed to MI. Intravenous injection of IL-11 activated signal transducer and activator of transcription 3 (STAT3), a downstream signaling molecule of glycoprotein 130, in cardiomyocytes in vivo, suggesting that cardiac myocytes are target cells of IL-11 in the hearts. Twenty-four hours after coronary ligation, IL-11 was administered intravenously, followed by consecutive administration every 24 hours for 4 days. IL-11 treatment reduced fibrosis area 14 days after MI, attenuating cardiac dysfunction. Consistent with a previous report that STAT3 exhibits antiapoptotic and angiogenic activity in the heart, IL-11 treatment prevented apoptotic cell death of the bordering myocardium adjacent to the infarct zone and increased capillary density at the border zone. Importantly, cardiac-specific ablation of STAT3 abrogated IL-11-mediated attenuation of fibrosis and was associated with left ventricular enlargement. Moreover, with the use of cardiac-specific transgenic mice expressing constitutively active STAT3, cardiac STAT3 activation was shown to be sufficient to prevent adverse cardiac remodeling.
IL-11 attenuated cardiac fibrosis after MI through STAT3. Activation of the IL-11/glycoprotein 130/STAT3 axis may be a novel therapeutic strategy against cardiovascular diseases.
Background: Avelumab, durvalumab, and atezolizumab are anti-programmed death-ligand 1 (PD-L1) antibodies approved for clinical application in Japan. Despite targeting the same molecule, avelumab ...elicits a different frequency of infusion-related reactions (IRRs) compared with durvalumab and atezolizumab, leading to differences in premedication recommendations. This study aimed to collect information to verify the relationship during IRRs and the characteristics of antibody molecules, by investigating the frequency of IRRs caused by three types of antibodies and the actual status of prophylactic measures. Methods: This single-center, retrospective observational study collected the medical records of 73 patients who received avelumab, durvalumab, or atezolizumab at Osaka University Hospital. Results: The frequency of IRRs was 50.0% (12/24) for avelumab, 31.0% (8/27) for durvalumab, and 18.2% (4/22) for atezolizumab. The IRRs were grade 2 in seven patients and grade 1 in five patients treated with avelumab, grade 2 in six patients and grade 1 in two patients treated with durvalumab, and grade 1 in all patients treated with atezolizumab. Among patients in whom symptoms were observed during the first administration, measures were taken to prevent IRRs for the second administration, but cases were confirmed in which symptoms reappeared, especially in patients who received durvalumab. Conclusion: Our findings indicate that the frequency of IRRs due to anti-PD-L1 antibodies is higher than that previously reported in clinical trials and different modifications in antibody molecules may affect the difference in IRR frequency.
Abstract
Runt-related transcription factor 2 (Runx2), a regulator of osteoblast differentiation, is pathologically involved in vascular calcification; however, the significance of Runx2 in cardiac ...homeostasis remains unclear. Here, we investigated the roles of Runx2 in cardiac remodeling after myocardial infarction (MI). The expression of Runx2 mRNA and protein was upregulated in murine hearts after MI. Runx2 was expressed in heart-infiltrating myeloid cells, especially in macrophages, at the border zone of post-infarct myocardium. To analyze the biological functions of Runx2 in cardiac remodeling, myeloid cell-specific
Runx2
deficient (CKO) mice were exposed to MI. After MI, ventricular weight/tibia length ratio was increased in CKO mice, concomitant with severe cardiac dysfunction. Cardiac fibrosis was exacerbated in CKO mice, consistent with the upregulation of collagen 1a1 expression. Mechanistically, immunohistochemical analysis using anti-CD31 antibody showed that capillary density was decreased in CKO mice. Additionally, conditioned culture media of myeloid cells from Runx2 deficient mice exposed to MI induced the tube formation of vascular endothelial cells to a lesser extent than those from control mice. RNA-sequence showed that the expression of pro-angiogenic or anti-angiogenic factors was altered in macrophages from Runx2-deficient mice. Collectively,
Runx2
+
myeloid cells infiltrate into post-infarct myocardium and prevent adverse cardiac remodeling, at least partially, by regulating endothelial cell function.
Excessive levels of reactive oxygen species (ROS) and impaired Ca2+ homeostasis play central roles in the development of multiple cardiac pathologies, including cell death during ischemia-reperfusion ...(I/R) injury. In several organs, treatment with 2-aminoethoxydiphenyl borate (2-APB) was shown to have protective effects, generally believed to be due to Ca2+ channel inhibition. However, the mechanism of 2-APB-induced cardioprotection has not been fully investigated. Herein we investigated the protective effects of 2-APB treatment against cardiac pathogenesis and deciphered the underlying mechanisms. In neonatal rat cardiomyocytes, treatment with 2-APB was shown to prevent hydrogen peroxide (H2O2) -induced cell death by inhibiting the increase in intracellular Ca2+ levels. However, no 2-APB-sensitive channel blocker inhibited H2O2-induced cell death and a direct reaction between 2-APB and H2O2 was detected by 1H-NMR, suggesting that 2-APB chemically scavenges extracellular ROS and provides cytoprotection. In a mouse I/R model, treatment with 2-APB led to a considerable reduction in the infarct size after I/R, which was accompanied by the reduction in ROS levels and neutrophil infiltration, indicating that the anti-oxidative properties of 2-APB plays an important role in the prevention of I/R injury in vivo as well. Taken together, present results indicate that 2-APB treatment induces cardioprotection and prevents ROS-induced cardiomyocyte death, at least partially, by the direct scavenging of extracellular ROS. Therefore, administration of 2-APB may represent a promising therapeutic strategy for the treatment of ROS-related cardiac pathology including I/R injury.
HECW2‐related disorder in four Japanese patients Yanagishita, Tomoe; Hirade, Takuya; Shimojima Yamamoto, Keiko ...
American journal of medical genetics. Part A,
October 2021, Letnik:
185, Številka:
10
Journal Article
Recenzirano
The HECT, C2, and WW domain containing E3 ubiquitin protein ligase 2 gene (HECW2) is involved in protein ubiquitination. Several genes associated with protein ubiquitination have been linked to ...neurodevelopmental disorders. HECW2‐related disorder has been established through the identification of de novo variants in HECW2 in patients with neurodevelopmental disorders with hypotonia, seizures, and absent language. Recently, we identified novel HECW2 variants in four Japanese patients with neurodevelopmental disorders. Regarding motor development, two of the patients cannot walk, whereas the other two can walk with an unsteady gait, owing to hypotonia. All HECW2 variants, including those that were previously reported, are missense, and no loss‐of‐function variants have been identified. Most of the identified variants are located around the HECT domain. These findings suggest that the dominant negative effects of missense variants around the HECT domain may be the mechanism underlying HECW2‐related disorder.
Mammalian cardiomyocytes substantially lose proliferative capacity immediately after birth, limiting adult heart regeneration after injury. However, clinical myocarditis appears to be self-limiting ...with tissue-reparative properties. Here, we investigated the molecular mechanisms underlying the recovery from myocarditis with regard to cardiomyocyte proliferation using an experimental autoimmune myocarditis (EAM) model. Three weeks after EAM induction (EAM3w), cardiac tissue displayed infiltration of inflammatory cells with cardiomyocyte apoptosis. However, by EAM5w, the myocardial damage was remarkably attenuated, associated with an increase in cardiomyocytes that were positively stained with cell cycle markers at EAM3w. Cardiomyocyte fate mapping study revealed that the proliferating cardiomyocytes primarily derived from pre-existing cardiomyocytes. Signal transducer and activator of transcription 3 (STAT3) was robustly activated in cardiomyocytes during inflammation, accompanied by induction of interleukin-6 family cytokines. Cardiomyocyte-specific ablation of STAT3 gene suppressed the frequency of cycling cardiomyocytes in the recovery period without influencing inflammatory status, resulting in impaired tissue repair and cardiac dysfunction. Finally, microarray analysis revealed that the expression of regeneration-related genes, metallothioneins and clusterin, in cardiomyocytes was decreased by STAT3 gene deletion. These data show that adult mammalian cardiomyocytes restore regenerative capacity with cell cycle reentry through STAT3 as the heart recovers from myocarditis-induced cardiac damage.
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