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Heart failure (HF) is a prevalent cardiovascular disease with significant morbidity and mortality rates worldwide. Due to the intricate structure of the heart, diverse cell types, and the complex pathogenesis of HF, further in-depth investigation into the underlying mechanisms is required. The elucidation of the heterogeneity of cardiomyocytes and the intercellular communication network is particularly important. Traditional high-throughput sequencing methods provide an average measure of gene expression, failing to capture the "heterogeneity" between cells and impacting the accuracy of gene function knowledge. In contrast, single-cell sequencing techniques allow for the amplification of the entire genome or transcriptome at the individual cell level, facilitating the examination of gene structure and expression with unparalleled precision. This approach offers valuable insights into disease mechanisms, enabling the identification of changes in cellular components and gene expressions during hypertrophy associated with HF. Moreover, it reveals distinct cell populations and their unique roles in the HF microenvironment, providing a comprehensive understanding of the cellular landscape that underpins HF pathogenesis. This review focuses on the insights provided by single-cell sequencing techniques into the mechanisms underlying HF and discusses the challenges encountered in current cardiovascular research.
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We explored physiological effects of the sodium-glucose co-transporter-2 inhibitor empagliflozin on intact experimentally hypertrophic murine hearts following transverse aortic constriction (TAC). Postoperative drug (2-6 weeks) challenge resulted in reduced late Na+ currents, and increased phosphorylated (p-)CaMK-II and Nav1.5 but not total (t)-CaMK-II, and Na+/Ca2+ exchanger expression, confirming previous cardiomyocyte-level reports. It rescued TAC-induced reductions in echocardiographic ejection fraction and fractional shortening, and diastolic anterior and posterior wall thickening. Dual voltage- and Ca2+-optical mapping of Langendorff-perfused hearts demonstrated that empagliflozin rescued TAC-induced increases in action potential durations at 80% recovery (APD80), Ca2+ transient peak signals and durations at 80% recovery (CaTD80), times to peak Ca2+ (TTP100) and Ca2+ decay constants (Decay30-90) during regular 10-Hz stimulation, and Ca2+ transient alternans with shortening cycle length. Isoproterenol shortened APD80 in sham-operated and TAC-only hearts, shortening CaTD80 and Decay30-90 but sparing TTP100 and Ca2+ transient alternans in all groups. All groups showed similar APD80, and TAC-only hearts showed greater CaTD80, heterogeneities following isoproterenol challenge. Empagliflozin abolished or reduced ventricular tachycardia and premature ventricular contractions and associated re-entrant conduction patterns, in isoproterenol-challenged TAC-operated hearts following successive burst pacing episodes. Empagliflozin thus rescues TAC-induced ventricular hypertrophy and systolic functional, Ca2+ homeostatic, and pro-arrhythmogenic changes in intact hearts.
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Compuestos de Bencidrilo , Calcio , Glucósidos , Homeostasis , Animales , Compuestos de Bencidrilo/farmacología , Glucósidos/farmacología , Ratones , Calcio/metabolismo , Homeostasis/efectos de los fármacos , Masculino , Potenciales de Acción/efectos de los fármacos , Arritmias Cardíacas/metabolismo , Arritmias Cardíacas/tratamiento farmacológico , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Canal de Sodio Activado por Voltaje NAV1.5/metabolismo , Intercambiador de Sodio-Calcio/metabolismo , Aorta/efectos de los fármacos , Aorta/metabolismo , Aorta/cirugía , Ratones Endogámicos C57BL , Isoproterenol/farmacología , Modelos Animales de EnfermedadRESUMEN
BACKGROUND: 3', 5'-cyclic AMP (cAMP) regulates numerous cardiac functions. Various hormones and neurotransmitters elevate intracellular cAMP (i[cAMP]) in cardiomyocytes through activating GsPCRs (stimulatory-G-protein-coupled-receptors) and membrane-bound ACs (adenylyl cyclases). Increasing evidence has indicated that stimulating different GsPCRs and ACs exhibits distinct, even opposite effects, on cardiomyocyte viability. However, the underlying mechanisms are not fully understood. METHODS: We used molecular and pharmacological approaches to investigate how different GsPCR/cAMP signaling differentially regulate cardiomyocyte viability with in vitro, ex vivo, and in vivo models. RESULTS: For prodeath GsPCRs, we explored ß1AR (beta1-adrenergic receptor) and H2R (histamine-H2-receptor). We found that their prodeath effects were similarly dependent on AC5 activation, ATP release to the extracellular space via PANX1 (pannexin-1) channel, and extracellular ATP (e[ATP])-mediated signaling involving in P2X7R (P2X purinoceptor 7) and CaMKII (Ca2+/calmodulin-dependent protein kinase II). PANX1 phosphorylation at Serine 206 by cAMP-dependent-PKA (protein-kinase-A) promoted PANX1 activation, which was critical in ß1AR- or H2R-induced cardiomyocyte death in vitro and in vivo. ß1AR or H2R was localized proximately to PANX1, which permits ATP release. For prosurvival GsPCRs, we explored adenosine-A2-receptor (A2R), CGRPR (calcitonin-gene-related-peptide-receptor), and RXFP1 (relaxin-family peptide-receptor 1). Their prosurvival effects were dependent on AC6 activation, cAMP efflux via MRP4 (multidrug resistance protein 4), extracellular cAMP metabolism to adenosine (e[cAMP]-to-e[ADO]), and e[ADO]-mediated signaling. A2R, CGRPR, or RXFP1 was localized proximately to MRP4, which enables cAMP efflux. Interestingly, exogenously increasing e[cAMP] levels by membrane-impermeable cAMP protected against cardiomyocyte death in vitro and in ex vivo and in vivo mouse hearts with ischemia-reperfusion injuries. CONCLUSIONS: Our findings indicate that the functional diversity of different GsPCRs in cardiomyocyte viability could be achieved by their ability to form unique signaling complexes (signalosomes) that determine the fate of cAMP: either stimulate ATP release by activating PKA or directly efflux to be e[cAMP].
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AMP Cíclico , Miocitos Cardíacos , Ratones , Animales , AMP Cíclico/metabolismo , Miocitos Cardíacos/metabolismo , Adenosina/metabolismo , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Adenosina Trifosfato/metabolismo , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/metabolismo , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/farmacología , Péptidos/metabolismoRESUMEN
Background: Physiological and pathological stimuli result in distinct forms of cardiac hypertrophy, but the molecular regulation comparing the two, especially at the DNA methylation level, is not well understood. Methods: We conducted an in vitro study using human cardiomyocytes exposed to angiotensin II (AngII) and insulin-like growth factor 1 (IGF-1) to mimic pathologically and physiologically hypertrophic heart models, respectively. Whole genome DNA methylation patterns were profiled by the Infinium human MethylationEPIC platform with >850 K DNA methylation loci. Two external datasets were used for comparisons and qRT-PCR was performed for examining expression of associated genes of those identified DNA methylation loci. Results: We detected 194 loci that are significantly differentially methylated after AngII treatment, and 206 significant loci after IGF-1 treatment. Mapping the significant loci to genes, we identified 158 genes corresponding to AngII treatment and 175 genes to IGF-1 treatment. Using the gene-set enrichment analysis, the PI3K-Akt signaling pathway was identified to be significantly enriched for both AngII and IGF-1 treatment. The Hippo signaling pathway was enriched after IGF-1 treatment, but not for AngII treatment. CDK6 and RPTOR are components of the PI3K-Akt pathway but have different DNA methylation patterns in response to AngII and IGF-1. qRT-PCR confirmed the different gene expressions of CDK6 and PRTOR. Conclusion: Our study is pioneering in profiling epigenome DNA methylation changes in adult human cardiomyocytes under distinct stress conditions: pathological (AngII) and physiological (IGF-1). The identified DNA methylation loci, genes, and pathways might have the potential to distinguish between pathological and physiological cardiac hypertrophy.
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Background: Sedentary behavior is associated with an increased risk for adverse health outcomes, including cardiovascular disease (CVD), independent of physical activity status. Little is known about this relationship in an ethnically diverse population. The objective of our study is to assess the effects of leisure time and occupational sedentary behavior on multiple cardiovascular outcomes in a multi-ethnic cohort. Methods: The Multi-Ethnic Study of Atherosclerosis (MESA) includes 2619 Caucasian, 1495 Hispanic, 1891 Black, and 804 Chinese-American adults aged 45-84 years and free of clinical CVD at enrollment, Sedentary behavior was self-reported at baseline. Participants were followed for an average of 13.6 years, and 14 types of cardiovascular outcomes were ascertained. Hazards of each cardiovascular outcome were modeled with adjustment for potential confounders, including physical activity. Results: Every one hour per day increase in leisure time sedentary behavior predicts a 6% increase in the adjusted hazards for CVD death ( P < 0.05). Every one hour increase in occupational sedentary time predicts a 21% and 20% decrease in the hazard for PVD and other revascularization, respectively ( P < 0.05). Conclusions: Leisure time sedentary behavior was associated with increased hazards for CVD death, but occupational sedentary time appears to be protective of peripheral vascular disease and other revascularization. Condensed Abstract: Sedentary behavior has been consistently associated with an increased risk for adverse health outcomes, including cardiovascular disease (CVD), independent of physical activity status. The Multi-Ethnic Study of Atherosclerosis (MESA) consists of a racially and ethnically diverse cohort of adults age 45-84, free from CVD at baseline. Greater levels of leisure time sedentary behavior predicted increased hazards for PVD and CVD death after an average follow up of 13.6 years whereas occupational sedentary behaviors predicted reduced PVD. These results underscore the importance of reducing time spent sitting in addition to advocating for meeting physical activity targets across ethnicities.
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BACKGROUND: Cyclic nucleotides play critical roles in cardiovascular biology and disease. PDE10A (phosphodiesterase 10A) is able to hydrolyze both cAMP and cGMP. PDE10A expression is induced in various human tumor cell lines, and PDE10A inhibition suppresses tumor cell growth. Chemotherapy drug such as doxorubicin (DOX) is widely used in chemotherapy. However, cardiotoxicity of DOX remains to be a serious clinical complication. In the current study, we aim to determine the role of PDE10A and the effect of PDE10A inhibition on cancer growth and cardiotoxicity induced by DOX. METHODS: We used global PDE10A knockout (KO) mice and PDE10A inhibitor TP-10 to block PDE10A function. DOX-induced cardiotoxicity was evaluated in C57Bl/6J mice and nude mice with implanted ovarian cancer xenografts. Isolated adult mouse cardiomyocytes and a human ovarian cancer cell line were used for in vitro functional and mechanistic studies. RESULTS: We found that PDE10A deficiency or inhibition alleviated DOX-induced myocardial atrophy, apoptosis, and dysfunction in C57Bl/6J mice. RNA sequencing study revealed a number of PDE10A-regulated signaling pathways involved in DOX-induced cardiotoxicity. PDE10A inhibition increased the death, decreased the proliferation, and potentiated the effect of DOX on various human cancer cells. Importantly, in nude mice with implanted ovarian cancer xenografts, PDE10A inhibition attenuated tumor growth while protecting DOX-induced cardiotoxicity. In isolated cardiomyocytes, PDE10A contributed to DOX-induced cardiomyocyte death via increasing Top2ß (topoisomerase 2ß) expression, mitochondrial dysfunction, and DNA damage by antagonizing cGMP/PKG (protein kinase G) signaling. PDE10A contributed to cardiomyocyte atrophy via potentiating FoxO3 (forkhead box O3) signaling via both cAMP/PKA (protein kinase A)- and cGMP/PKG-dependent signaling. CONCLUSIONS: Taken together, our study elucidates a novel role for PDE10A in cardiotoxicity induced by DOX and cancer growth. Given that PDE10A has been already proven to be a safe drug target, PDE10A inhibition may represent a novel therapeutic strategy in cancer therapy, with effects preventing DOX-induced cardiotoxicity and simultaneously antagonizing cancer growth.
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Cardiotoxicidad , Neoplasias Ováricas , Animales , Femenino , Humanos , Ratones , Apoptosis , Atrofia/complicaciones , Atrofia/metabolismo , Atrofia/patología , Cardiotoxicidad/metabolismo , Doxorrubicina/efectos adversos , Doxorrubicina/toxicidad , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Desnudos , Miocitos Cardíacos/metabolismo , Neoplasias Ováricas/metabolismo , Estrés Oxidativo , Hidrolasas Diéster Fosfóricas/genética , Hidrolasas Diéster Fosfóricas/metabolismoRESUMEN
BACKGROUND: While there is some evidence and conceptual plausibility that tobacco product use is associated with hypertension incidence and that this association varies by sex, extant longitudinal research had been conducted prior to the emergence of e-cigarette and dual e-cigarette and cigarette use. AIMS AND METHODS: Data were analyzed from the US Population Assessment of Tobacco and Health study for adults with no lifetime history of hypertension at wave 1 (2013-2014) who completed waves 2-4 follow-up surveys (2014-2018; n = 16 434). Sex-stratified weighted covariate-adjusted multivariable Cox regression models were used to examine the association between established current e-cigarette or cigarette exclusive or dual-use (as a time-varying and time-lagged regressor) and subsequent self-reported hypertension onset. RESULTS: Weighted cumulative hypertension incidence by wave 4 varied by waves 1-3 e-cigarette, cigarette, and dual use status in females (nonuse [incidence: 9.9%], exclusive e-cigarette use [11.8%], exclusive cigarette use [14.8%], dual-use [12.4%]; p = .003 for omnibus differences among all groups) but not males (nonuse [12.6%], exclusive e-cigarette use [9.7%], exclusive cigarette use [13.7%], dual-use [9.3%]; p = .231). Among females, exclusive cigarette (vs. no) use (hazard ratio: 1.69, 95%CI 1.21 to 2.34; p = .002), but not exclusive e-cigarette or dual-use, was significantly associated with subsequent hypertension. Dose-response models were suggestive that consistent exclusive e-cigarette or dual-use versus nonuse across multiple may be associated with hypertension among females, but results were nonsignificant. CONCLUSIONS: The association of e-cigarette, cigarette, and dual use with hypertension may differ by sex, whereby exclusive cigarette use could be a prospective risk factor for subsequent self-reported hypertension in US adult females. IMPLICATIONS: This nationally representative cohort study provides the very first evidence of whether there are prospective associations of established e-cigarette and cigarette use and dual use with future hypertension onset among US adult females and males. We found that exclusive cigarette smoking was associated with an increased risk of incident hypertension among females, but not males. We observed a trend of a dose-response relationship between e-cigarette use and risk of incident hypertension among female exclusive e-cigarette users or dual e-cigarette and cigarette users. Our study will contribute to understanding the chronic health risks of vaping to prevent the potential long-term e-cigarette use-related health burden.
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Sistemas Electrónicos de Liberación de Nicotina , Hipertensión , Productos de Tabaco , Vapeo , Adulto , Humanos , Masculino , Femenino , Estudios de Cohortes , Autoinforme , Caracteres Sexuales , Incidencia , Hipertensión/epidemiología , Vapeo/efectos adversos , Vapeo/epidemiologíaRESUMEN
Introduction: Despite strong public support, organ donor registration rates (RR) continue to lag while need only grows. In the United States, the traditional registration site is the Department of Motor Vehicles (DMV), however Primary care provider (PCP) offices have been considered as alternate locations for increasing RR. Methods: Twelve PCP offices across 2 New York Counties were subjected to a control week where participants received only a registration opportunity and an intervention week with the addition of a motivational poster and informational brochure. Zip code level sociodemographic data were obtained for each site. RR from the DMV over the same period served as historical control. Results: There were 1292 participants in the control phase and 1099 in the experimental phase. New registration rate for the control was 33.8% (289/897); experimental phase 7.88% (61/769); DMV registration 21.02% (1902/9050). The intervention was associated with a significant decrease in registrations (OR 0.181 (95% CI 0.135-0.244, P < 0.001)). Offices were clustered based on sociodemographic factors and regressed in 2 clusters. Lower educational attainment was associated with lower registration in the first but not second cluster (OR = 0.948 (0.923-0.974, P < 0.001)). Conclusions: This study provided evidence that PCP offices were a feasible site for organ donor registration and calls into question the efficacy of written materials-only interventions for increasing organ donor RR. It reiterated the negative effect of lower educational attainment on registration and suggested future studies focus on more active methods of engagement.
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Obtención de Tejidos y Órganos , Humanos , Estados Unidos , New York , Sistema de Registros , Donantes de Tejidos , Atención Primaria de SaludRESUMEN
Background cGMP-hydrolyzing phosphodiesterase type 5 (PDE5) regulates vascular smooth muscle cell (SMC) contraction by antagonizing cGMP-dependent protein kinase I (PKGI)-dependent SMC relaxation. SMC contractile dysfunction is implicated in the pathogenesis of aortic aneurysm. PDE5 inhibitors have been used for treating erectile dysfunction, such as drug Viagra (sildenafil). However, a few clinical cases have reported the association of Viagra usage with aortic dissection, and reduced PDE5A expression was found in human aortic aneurysm tissues. Therefore, we aimed to investigate the effect of sildenafil on experimental abdominal aortic aneurysm (AAA), the most common form of aortic aneurysm in elderly men. Methods and Results AAA was induced in C57BL/6J male mice by periaortic elastase in combination with blocking elastin/collagen formation via 3-aminopropionitrile fumarate salt for 35 days. PDE5A protein levels detected by immunostaining were significantly reduced in mouse AAA. Sildenafil application in drinking water significantly aggravated aortic wall dilation and elastin degradation with pre-existing moderate AAA. The phosphorylation level of myosin light chain 2 at Ser19, a biochemical marker of SMC contraction, was significantly reduced by sildenafil in AAA. Proximity ligation assay further revealed that the interaction between cGMP and PKGI was significantly increased by sildenafil in AAA, suggesting an elevation of PKGI activation in AAA. Conclusions Sildenafil treatment aggravated the degradation of elastin fibers and progression of experimental AAA by dysregulating cGMP and contractile signaling in SMCs. Our findings may raise the caution of clinical usage of Viagra in aneurysmal patients.
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Aneurisma de la Aorta Abdominal , Elastina , Anciano , Animales , Aorta Abdominal/metabolismo , Aneurisma de la Aorta Abdominal/metabolismo , Modelos Animales de Enfermedad , Elastina/metabolismo , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Citrato de Sildenafil/farmacologíaRESUMEN
Sunitinib is the first-line drug for treating renal cell carcinoma (RCC), and it functions mainly through inhibition of tumor angiogenesis. However, the patients may become insensitive or develop resistance toward sunitinib treatment, but the underlying mechanisms have not yet been fully elucidated. Herein, it was found that sunitinib could have adverse effects of promoting RCC progression by increasing vascular mimicry (VM) formation of RCC cells. Mechanism dissection revealed that sunitinib can increase the expression of a long non-coding RNA (lncRNA), lncRNA-ECVSR, thereby enhancing the stability of estrogen receptor ß (ERß) mRNA. Subsequently, the increased ERß expression can then function via transcriptional up-regulation of Hif2-α. Notably, sunitinib-increased lncRNA-ECVSR/ERß/Hif2-α signaling resulted in an increased cancer stem cell (CSC) phenotype, thereby promoting VM formation. Furthermore, the sunitinib/lncRNA-ECVSR-increased ERß expression can transcriptionally regulate lncRNA-ECVSR expression via a positive-feedback loop. Supportively, preclinical studies using RCC mouse xenografts demonstrated that combining sunitinib with the small molecule anti-estrogen PHTPP can increase sunitinib efficacy with reduced VM formation. Collectively, the findings of this study may aid in the development of potential biomarker(s) and novel therapies to better monitor and suppress RCC progression.
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Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Carcinoma de Células Renales/tratamiento farmacológico , Receptor beta de Estrógeno/genética , ARN Largo no Codificante/genética , Sunitinib/farmacología , Animales , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/patología , Diferenciación Celular/efectos de los fármacos , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Ratones , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/patología , Neovascularización Patológica/tratamiento farmacológico , Neovascularización Patológica/genética , Neovascularización Patológica/patología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: The complexity of physical activity (PA) and DNA methylation interaction in the development of cardiovascular disease (CVD) is rarely simultaneously investigated in one study. We examined the role of DNA methylation on the association between PA and CVD. RESULTS: The Multi-Ethnic Study of Atherosclerosis (MESA) cohort Exam 5 data with 1065 participants free of CVD were used for final analysis. The quartile categorical total PA variable was created by activity intensity (METs/week). During a median follow-up of 4.0 years, 69 participants developed CVD. Illumina HumanMethylation450 BeadChip was used to provide genome-wide DNA methylation profiles in purified human monocytes (CD14+). We identified 23 candidate DNA methylation loci to be associated with both PA and CVD. We used the structural equation modeling (SEM) approach to test the complex relationships among multiple variables and the roles of mediators. Three of the 23 identified loci (corresponding to genes VPS13D, PIK3CD and VPS45) remained as significant mediators in the final SEM model along with other covariates. Bridged by the three genes, the 2nd PA quartile (ß = - 0.959; 95%CI: - 1.554 to - 0.449) and the 3rd PA quartile (ß = - 0.944; 95%CI: - 1.628 to - 0.413) showed the greatest inverse associations with CVD development, while the 4th PA quartile had a relatively weaker inverse association (ß = - 0.355; 95%CI: - 0.713 to - 0.124). CONCLUSIONS: The current study is among the first to simultaneously examine the relationships among PA, DNA methylation, and CVD in a large cohort with long-term exposure. We identified three DNA methylation loci bridged the association between PA and CVD. The function of the identified genes warrants further investigation in the pathogenesis of CVD.
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Aterosclerosis , Enfermedades Cardiovasculares , Aterosclerosis/genética , Enfermedades Cardiovasculares/genética , Metilación de ADN , Etnicidad , Ejercicio Físico , Humanos , Factores de RiesgoRESUMEN
Cyclic nucleotide phosphodiesterases (PDEs), through the degradation of cyclic nucleotides, play critical roles in cardiovascular biology and disease. PDE10A is able to hydrolyze both cAMP and cGMP. Its high expression in medium spiny neurons of the human striatum has led to the development of several PDE10A inhibitors with the intent to treat various psychiatric/neurodegenerative disorders, such as schizophrenia and Huntington's disease. Our previous study has reported the upregulation of PDE10A expression in failing hearts and demonstrated the protective effects of PDE10A deficiency/inhibition against cardiac hypertrophy, fibrosis, and dysfunction in mouse models of heart failure. Doxorubicin (DOX) is an effective chemotherapeutic agent against a variety of cancers. While its therapeutic utility is limited by the development of dose-dependent cardiotoxicity. In the current study, we aim to determine the role of PDE10A in cancer and cardiotoxicity induced by DOX. We found that PDE10A inhibition or deficiency alleviated DOX-induced cardiotoxicity in vivo, as well as cardiac myocyte (CM) death and atrophy in vitro. In ovarian cancer cells, PDE10A inhibition induced cell death and reduced cell proliferation; as well as potentiated the effect of DOX on antagonizing cancer cells. Interestingly, in nude mice with ovarian cancer xenografts, PDE10A inhibition attenuated ovarian tumor growth while protected DOX-induced cardiotoxicity. RNAseq and bioinformatics analysis uncovered a number of PDE10A-regulated signaling pathways and cellular processes involved in DOX-induced cardiotoxicity. Mechanistic studies further revealed that PDE10A regulates CM death and atrophy via different mechanistic actions: regulating CM death via a cGMP-dependent while cAMP-independent mechanism; and regulating CM atrophy via a mechanism dependent on both cGMP and cAMP. Several PDE10A inhibitors have been tested in humans and successfully passed phase I clinical trials for safety. Thus, our findings suggest that PDE10A may be a safe "druggable" target for cancer therapy by simultaneously preventing DOX-induced cardiotoxicity and antagonizing tumor growth.
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Abdominal aortic aneurysm (AAA) is characterized by aorta dilation due to wall degeneration, which mostly occurs in elderly males. Vascular aging is implicated in degenerative vascular pathologies, including AAA. Cyclic nucleotide phosphodiesterases, by hydrolyzing cyclic nucleotides, play critical roles in regulating vascular structure remodeling and function. Cyclic nucleotide phosphodiesterase 1C (PDE1C) expression is induced in dedifferentiated and aging vascular smooth muscle cells (SMCs), while little is known about the role of PDE1C in aneurysm. We observed that PDE1C was not expressed in normal aorta but highly induced in SMC-like cells in human and murine AAA. In mouse AAA models induced by Angiotensin II or periaortic elastase, PDE1C deficiency significantly decreased AAA incidence, aortic dilation, and elastin degradation, which supported a causative role of PDE1C in AAA development in vivo. Pharmacological inhibition of PDE1C also significantly suppressed preestablished AAA. We showed that PDE1C depletion antagonized SMC senescence in vitro and/or in vivo, as assessed by multiple senescence biomarkers, including senescence-associated ß-galactosidase activity, γ-H2AX foci number, and p21 protein level. Interestingly, the role of PDE1C in SMC senescence in vitro and in vivo was dependent on Sirtuin 1 (SIRT1). Mechanistic studies further showed that cAMP derived from PDE1C inhibition stimulated SIRT1 activation, likely through a direct interaction between cAMP and SIRT1, which leads to subsequent up-regulation of SIRT1 expression. Our findings provide evidence that PDE1C elevation links SMC senescence to AAA development in both experimental animal models and human AAA, suggesting therapeutical significance of PDE1C as a potential target against aortic aneurysms.
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Aneurisma de la Aorta Abdominal/enzimología , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 1/metabolismo , Regulación Enzimológica de la Expresión Génica/fisiología , Angiotensina II/toxicidad , Animales , Aneurisma de la Aorta Abdominal/inducido químicamente , Aneurisma de la Aorta Abdominal/genética , Biomarcadores , Senescencia Celular , AMP Cíclico , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 1/genética , Inhibidor p21 de las Quinasas Dependientes de la Ciclina , Histonas , Masculino , Ratones , Ratones Noqueados para ApoE , ARN Mensajero/genética , ARN Mensajero/metabolismo , Sirtuina 1/genética , Sirtuina 1/metabolismo , Regulación hacia Arriba , beta-Galactosidasa/genética , beta-Galactosidasa/metabolismoRESUMEN
Following their introduction a decade ago, electronic cigarettes (e-cigarettes) have grown in popularity. Given their novelty, knowledge of the health consequences of e-cigarette use remains limited. Epidemiologic studies have not comprehensively explored associations between e-cigarette use and hypertension, a highly prevalent health condition and major contributor to cardiovascular disease burden. In this study, cross-sectional associations of cigarette smoking and e-cigarette use (vaping) with self-reported diagnosed hypertension were evaluated among 19,147 18-55 year old respondents in Wave 3 (2015-2016) of the Population Assessment of Tobacco and Health Study. Multivariable analyses first modeled smoking and vaping as separate 2-category variables, then as a 6-category composite variable accounting for former smoking. After adjusting for potential confounders, current vaping (aOR = 1.31; 95%CI: 1.05-1.63) and current smoking (aOR = 1.27; 95%CI: 1.10-1.47) were both associated with higher odds of hypertension. In analyses modeling smoking and vaping compositely, respondents who were concurrently smoking and vaping had the highest odds of hypertension (aOR = 1.77; 95%CI: 1.32-2.39 [referent: never smokers]). These results differ somewhat from prior epidemiologic studies of vaping and respiratory outcomes, which consistently report smaller point estimates for current vaping than for current smoking. Our findings reinforce the uncertainty surrounding long-term health consequences of vaping, as well as highlight important distinctions between respiratory and cardiovascular outcomes when considering the harm reduction potential of e-cigarettes.
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INTRODUCTION: Flavors other than tobacco flavor have been identified as a major reason for electronic nicotine delivery system (ENDS) initiation in youth and are thought to contribute to the continued use of ENDS in users of all ages. Our previous research showed a significant association between overall ENDS use and COPD. This study aims to identify the association of ENDS flavor categories with self-reported COPD. METHODS: The data analysis included 4909 adults from Population Assessment of Tobacco and Health (PATH) Wave 4 data who were ever established ENDS users and responded to an item about diagnosis of COPD. Weighted multivariable logistic regression models were used to examine the association between different ENDS flavors and self-reported COPD considering complex sampling design. RESULTS: Among 4909 ever established ENDS users, 418 adults (weighted percentage 9.8%) had self-reported COPD. Self-reported COPD prevalence differed between different ENDS flavor categories, with the highest (weighted percentage 19.9%) occurring among tobacco flavor users. Compared to non-tobacco flavor categories, tobacco flavor category showed significantly higher association with self-reported COPD (AOR=2.05; 95% CI: 1.20-3.53), after adjusting for potential confounding variables. No significant associations with self-reported COPD were found for other examined ENDS flavor categories including menthol/mint, fruit, candy/ desserts/other-sweets, and other flavors, compared to their corresponding non-users. CONCLUSIONS: Tobacco flavored ENDS use was significantly associated with self-reported COPD. Future studies are needed to confirm the biological and epidemiological association of flavored ENDS use with COPD.
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Abdominal aortic aneurysm (AAA), commonly occurring in the aged population, is a degenerative disease that dilate and weaken infrarenal aorta due to progressive degeneration of aortic wall integrity. Vinpocetine, a derivative of alkaloid vincamine, has long been used for cerebrovascular disorders and cognitive impairment in the aged population. Recent studies have indicated that vinpocetine antagonizes occlusive vascular disorders such as intimal hyperplasia and atherosclerosis. However, its role in vascular degenerative disease AAA remains unexplored. Herein, we determined the effect of vinpocetine on the formation of AAA as well as the intervention of pre-existing moderate AAA. AAA was induced by periaortic elastase application in C57BL/6J mice. Systemic vinpocetine treatment was applied daily via intraperitoneal injection. We showed that vinpocetine pre-treatment remarkably attenuated aneurysmal dilation assessed by diameter and volume. More importantly, vinpocetine also significantly suppressed the progression of pre-existing moderate AAA in a post-intervention model. Vinpocetine improved multiple cellular and molecular changes associated with AAA, such as elastin degradation, media smooth muscle cell depletion, collagen fibers remodeling and macrophage infiltration in aneurysmal tissues. Vinpocetine potently suppressed tumor necrosis factor-α-induced nuclear factor kappa-light-chain-enhancer of activated B cells activation and proinflammatory mediator expression in primary cultured macrophages in vitro, as well as in the aorta wall in vivo, suggesting vinpocetine conferred anti-AAA effect at least partially via the inhibition of inflammation. Taken together, our findings reveal a novel role of vinpocetine in AAA formation, development and progression. Given the excellent safety profile of vinpocetine, the present study suggests vinpocetine may be a novel therapeutic agent for AAA prevention and treatment.
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Aneurisma de la Aorta Abdominal/tratamiento farmacológico , Sustancias Protectoras/uso terapéutico , Alcaloides de la Vinca/uso terapéutico , Animales , Aneurisma de la Aorta Abdominal/patología , Células Cultivadas , Dilatación Patológica , Progresión de la Enfermedad , Elastina/metabolismo , Inflamación/patología , Macrófagos/efectos de los fármacos , Macrófagos/patología , Ratones Endogámicos C57BL , Miocitos del Músculo Liso/metabolismo , FN-kappa B/metabolismo , Sustancias Protectoras/farmacología , Proteoglicanos/metabolismo , Proteolisis/efectos de los fármacos , Alcaloides de la Vinca/farmacologíaRESUMEN
BACKGROUND AND AIMS: CYP17 inhibitors can block androgen production both intratumorally and systemically, thus attenuating the progression of prostate cancer (PCa). Many randomized controlled trials (RCTs) showed promising results that men with metastatic castration-resistant PCa (mCRPC) might benefit from treatment with CYP17 inhibitors such as abiraterone acetate and orteronel. The goal of this study was to evaluate the efficacy of CYP17 inhibitors for the prognosis in patients with mCRPC. MATERIALS AND METHODS: Studies were identified in PubMed/MEDLINE, the Cochrane Library, and the Web of Science. The RCTs with mCRPC patients focusing on the efficacy of CYP17 inhibitors were involved. Then, we analyzed the patients' prognosis such as overall survival (OS) and radiographic progression-free survival (RPFS). RESULTS: A meta-analysis of the pooled data from seven randomized Phase III clinical trials was performed to compare 5516 mCRPC patients with CYP17 inhibitors versus that with placebo. Compared to placebo, the CYP17 inhibitors significantly increased the OS (pooled hazard ratios [HR]: 0.816, 95% confidence interval [CI]: 0.750-0.887), RPFS (pooled HR: 0.647, 95% CI: 0.557-0.752), and time to prostate-specific antigen (PSA) progression (pooled HR: 0.599, 95% CI: 0.517-0.693). Additional endpoints such as PSA response rate, objective response assessed by Response Evaluation Criteria in Solid Tumors, and time to initiation of chemotherapy were included in this study and were found having significant improvement with CYP17 inhibitors compared to placebo. CONCLUSION: This research showed that CYP17 inhibitors had a significant improvement on prognosis of patients with mCRPC within a relative safety profile both in pre- and post-chemotherapy trials. These expected results provide evidence for the use of CYP17 inhibitors to treat mCRPCs.
Asunto(s)
Acetato de Abiraterona/uso terapéutico , Inhibidores Enzimáticos del Citocromo P-450/uso terapéutico , Antígeno Prostático Específico/sangre , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Esteroide 17-alfa-Hidroxilasa/antagonistas & inhibidores , Ensayos Clínicos Fase III como Asunto , Humanos , Masculino , Pronóstico , Neoplasias de la Próstata Resistentes a la Castración/patología , Ensayos Clínicos Controlados Aleatorios como Asunto , Tasa de SupervivenciaRESUMEN
We examined the prevalence of home smoking and vaping restrictions among US adults, and compared home policy differences for smoking and vaping among vapers, smokers, and dual users. Secondary data from the Population Assessment of Tobacco and Health (PATH) Study Wave 3 (2015-2016) with 28,148 adults were analyzed using weighted multivariable logistic regression models that account for complex sampling design to compare differences in home policies among non-users, vapers only, smokers only, and dual users. Compared to never-users, current vapers who were ex-smokers and dual users were more likely to allow home vaping (aOR = 11.06, 95% CI: 8.04-15.21; aOR = 6.44, 95% CI: 5.01-8.28) and smoking (aOR = 1.62, 95% CI: 1.19-2.22; aOR = 3.58, 95% CI: 2.88-4.45). Current smokers were more likely to allow vaping (aOR = 3.53, 95% CI: 3.06-4.06) and smoking (aOR = 4.27, 95% CI: 3.73-4.89) inside the home than never-users. Current vapers who never smoked were more likely to allow vaping inside the home than never-users (aOR = 2.45, 95% CI: 1.53-3.93). Vapers reported much lower rates of vape-free home policies relative to both their smoke-free home policies and to vape-free home policies among smokers. Vapers may be using e-cigarettes in hopes of harm reduction, but interpreting "harm reduction" as safe, thus exposing non-users in their homes to second- and thirdhand aerosols. This underscores the need to healthcare providers to extend intervention with vapers to include implementing vape-free home policies.
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Sistemas Electrónicos de Liberación de Nicotina , Política para Fumadores , Vapeo , Adulto , Humanos , Fumadores , NicotianaRESUMEN
Renal cell carcinoma (RCC) is one of the most lethal urological tumors. Using sunitinib to improve the survival has become the first-line therapy for metastatic RCC patients. However, the occurrence of sunitinib resistance in the clinical application has curtailed its efficacy. Here we found TR4 nuclear receptor might alter the sunitinib resistance to RCC via altering the TR4/lncTASR/AXL signaling. Mechanism dissection revealed that TR4 could modulate lncTASR (ENST00000600671.1) expression via transcriptional regulation, which might then increase AXL protein expression via enhancing the stability of AXL mRNA to increase the sunitinib resistance in RCC. Human clinical surveys also linked the expression of TR4, lncTASR, and AXL to the RCC survival, and results from multiple RCC cell lines revealed that targeting this newly identified TR4-mediated signaling with small molecules, including tretinoin, metformin, or TR4-shRNAs, all led to increase the sunitinib sensitivity to better suppress the RCC progression, and our preclinical study using the in vivo mouse model further proved tretinoin had a better synergistic effect to increase sunitinib sensitivity to suppress RCC progression. Future successful clinical trials may help in the development of a novel therapy to better suppress the RCC progression.
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Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Carcinoma de Células Renales/tratamiento farmacológico , Neoplasias Renales/tratamiento farmacológico , Proteínas Proto-Oncogénicas/genética , ARN Largo no Codificante/genética , Proteínas Tirosina Quinasas Receptoras/genética , Receptores de Esteroides/metabolismo , Receptores de Hormona Tiroidea/metabolismo , Sunitinib/farmacología , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/patología , Hipoxia de la Célula/genética , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Movimiento Celular/genética , Progresión de la Enfermedad , Resistencia a Antineoplásicos/efectos de los fármacos , Resistencia a Antineoplásicos/genética , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Neoplasias Renales/genética , Neoplasias Renales/patología , Metformina/farmacología , Metformina/uso terapéutico , Ratones , ARN Largo no Codificante/metabolismo , ARN Interferente Pequeño/metabolismo , Receptores de Esteroides/genética , Receptores de Hormona Tiroidea/genética , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Sunitinib/uso terapéutico , Tretinoina/farmacología , Tretinoina/uso terapéutico , Ensayos Antitumor por Modelo de Xenoinjerto , Tirosina Quinasa del Receptor AxlRESUMEN
PURPOSE: The question of whether orthotopic neobladder (ONB) reconstruction is superior to ileal conduit diversion (ICD) with respect to health-related quality of life (HRQoL) remains controversial. The goal of this study is to perform a meta-analysis to compare post-ICD and post-ONB HRQoL in patients with bladder cancer. METHODS: A systematic search of Medline, Embase, the Cochrane Central Register of Controlled Trials, and the annual congress abstracts of the European Association of Urology (EAU), the American Urological Association (AUA) and the Société Internationale d'Urologie (SIU) up to June 2017 was conducted to identify all relevant clinical trials using validated questionnaires to assess HRQoL. A systematic review and meta-analysis were then performed. RESULTS: A total of 2507 patients from 26 eligible studies were included. Meta-analyses showed significant differences favouring ONB patients in global health status (WMD + 9.13, p = 0.004), physical functioning (WMD + 11.57, p = 0.0001), role functioning (WMD + 9.64, p = 0.002), and social functioning (WMD + 6.81, p = 0.03) based on the EORTC-QLQ-C30 questionnaire and in the total score of FACT questionnaire (WMD + 6.80, p = 0.001). However, ONB patients were more likely to have postoperative urinary symptoms than ICD patients (WMD - 22.19, p = 0.0001). CONCLUSIONS: ONB patients are more likely to have a better global health status than ICD patients. Regardless of the type of urinary diversion (UD) surgery, a gradual improvement in HRQoL over preoperative status tended to stabilise after 12 months postoperatively.