Background: Left atrial (LA) and left ventricular (LV) remodeling are associated with atrial fibrillation (AF). The prospective associations of impairment in cardiac mechanical function, as assessed by speckle-tracking echocardiography, with incident AF are less clear. Methods: In the Cardiovascular Health Study, a community-based cohort of older adults, participants free of AF with echocardiograms of adequate quality for speckle-tracking were included. We evaluated the associations of indices of cardiac mechanics (LA reservoir strain, LV longitudinal strain, and LV early diastolic strain rate) with incident AF. Results: Of 4,341 participants with strain imaging, participants with lower LA reservoir strain were older, had more cardiometabolic risk factors, and had lower renal function at baseline. Over median follow-up of 10 years, 497 (11.4%) participants developed AF. Compared with the highest quartile of LA reservoir strain, the lowest quartile of LA reservoir strain was associated with higher risk of AF after covariate adjustment, including LA volume and LV longitudinal strain (HR: 1.80, 95% CI: 1.31-2.45, P <0.001). The association of LA reservoir strain and AF was stronger in subgroups with higher blood pressure, NT-proBNP, and LA volumes. There were no associations of LV longitudinal strain and LV early diastolic strain rate with incident AF after adjustment for LA reservoir strain. Conclusion: Lower LA reservoir strain was associated with incident AF, independent of LV mechanics, and with stronger associations in high-risk subgroups. These findings suggest that mechanical dysfunction of the LA precedes the development of AF. Therapies targeting LA mechanical dysfunction may prevent progression to AF.
Ravi B. Patel, Joseph A. Delaney, Mo Hu, Harnish Patel, Jeanette Y. Cheng, John Gottdiener, Jorge R. Kizer, Gregory M. Marcus, Mintu P. Turakhia, Rajat Deo, Susan R. Heckbert, Bruce M. Psaty, Sanjiv J. Shah
In the aging population, lower urinary tract (LUT) dysfunction is common and often leads to storage and voiding difficulties classified into overlapping symptom syndromes. Despite prevalence and consequences of these syndromes, LUT disorders continue to be undertreated simply because there are few therapeutic options. LUT function and structure were assessed in aged (>25 months) male and female Fischer 344 rats randomized to oral treatment with a purine nucleoside phosphorylase (PNPase inhibitor) 8-aminoguanine (8-AG) for 6 weeks or vehicle. The bladders of aged rats exhibited multiple abnormalities: tactile insensitivity, vascular remodeling, reduced collagen-fiber tortuosity, increased bladder stiffness, abnormal smooth muscle morphology, swelling of mitochondria and increases in uro-damaging purine metabolites. Treatment of aged rats with 8-AG restored all evaluated histological, ultrastructural and physiological abnormalities toward that of a younger state. 8-AG, is an effective treatment that ameliorates key age-related structural and physiologic bladder abnormalities. Because PNPase inhibition blocks metabolism of inosine to hypoxanthine and guanosine to guanine, likely uro-protective effects of 8-AG are mediated by increased bladder levels of uro-protective inosine and guanosine and reductions in uro-damaging hypoxanthine and xanthine. These findings demonstrate 8-AG has translational potential for treating age-associated LUT dysfunctions and resultant syndromes in humans.
Lori A. Birder, Amanda Wolf-Johnston, Alan J. Wein, Fangzhou Cheng, Mara Grove-Sullivan, Anthony J. Kanai, Alan M. Watson, Donna Stolz, Simon C. Watkins, Anne M. Robertson, Diane Newman, Roger R. Dmochowski, Edwin K. Jackson
Focal adhesion kinase (FAK) is an important mediator of extracellular matrix-integrin mechano-signal transduction that regulates cell motility, survival, and proliferation. As such, FAK is being investigated as a potential therapeutic target for malignant and fibrotic diseases, and numerous clinical trials of FAK inhibitors are underway. The function of FAK in non-malignant non-motile epithelial cells is not well understood. We previously showed that hepatocytes demonstrated activated FAK near stiff collagen tracts in fibrotic liver. In this study, we examined the role of liver epithelial FAK by inducing fibrotic liver disease in mice with liver epithelial FAK deficiency. We found that mice that lack FAK in liver epithelial cells develop more severe liver injury and worse fibrosis as compared to controls. Increased fibrosis in liver epithelial FAK-deficient mice is linked to the activation of several pro-fibrotic pathways, including the hedgehog-smoothened pathway. FAK-deficient hepatocytes produce increased Indian hedgehog in a manner dependent on matrix stiffness. Furthermore, expression of the hedgehog receptor, smoothened, is increased in macrophages and biliary cells of hepatocyte-specific FAK-deficient fibrotic liver. These results indicate that liver epithelial FAK has important regulatory roles in the response to liver injury and progression of fibrosis.
Yun Weng, Tyler J. Lieberthal, Vivian X. Zhou, Maya Lopez-Ichikawa, Manuel Armas-Phan, Tristan K. Bond, Miya C. Yoshida, Won-Tak Choi, Tammy T. Chang
Protein phosphatase 2A is a ubiquitously expressed serine/threonine phosphatase which comprises a scaffold, a catalytic and multiple regulatory subunits and has been shown to be important in the expression of autoimmunity. We considered that a distinct subunit may account for the decreased production of interleukin-2 (IL-2) in people and mice with systemic autoimmunity. We show that the regulatory subunit PPP2R2D is increased in T cells from people with systemic lupus erythematosus and regulates IL-2 production. Mice lacking PPP2R2D only in T cells produce more IL-2 because the IL-2 gene and genes coding for IL-2 enhancing transcription factors remain open and the levels of the enhancer phosphorylated CREB are high. Mice with T cell-specific PPP2R2D deficiency display less systemic autoimmunity when exposed to a TLR7 stimulator. While genes related to regulatory T cell function do not change in the absence of PPP2R2D, regulatory T cells exhibit high suppressive function in vitro and in vivo. Because the ubiquitous expression of protein phosphatase 2A cannot permit systemic therapeutic manipulation, the identification of regulatory subunits able to control specific T cell functions opens the way for the development of novel, function-specific drugs.
Wenliang Pan, Amir Sharabi, Andrew P. Ferretti, Yinfeng Zhang, Catalina Burbano, Nobuya Yoshida, Maria G. Tsokos, George C. Tsokos
ZIP8 is a metal transporter with a role in manganese (Mn) homeostasis. A common genetic variant in ZIP8 (rs13107325; A391T) ranks in the top 10 of pleiotropic single nucleotide polymorphisms (SNP) identified in genome-wide association studies, including associations with an increased risk of schizophrenia, obesity, Crohn’s disease, and reduced blood Mn. Here, we used CRISPR/Cas9-mediated knock-in (KI) to generate a mouse model of ZIP8 A391T (mouse Zip8 393T-KI). Recapitulating the SNP association with blood Mn, blood Mn is reduced in Zip8 393T-KI mice. There is restricted abnormal tissue Mn homeostasis with decreases in liver and kidney Mn and reciprocal increase in biliary Mn to provide in vivo evidence of hypomorphic Zip8 function. Upon challenge in a chemical-induced colitis model, male Zip8 393T-KI mice exhibited enhanced disease susceptibility. ZIP8 391-Thr associated with reduced triantennary plasma N-glycan species in a population-based cohort to define a genotype-specific glycophenotype hypothesized to be linked to Mn-dependent glycosyltransferase activity. This glycophenotype was maintained in a cohort of Crohn’s disease patients. These data and the pleiotropic disease associations with ZIP8 391-Thr suggest underappreciated roles of Mn homeostasis in compex human disease.
Laxmi Sunuwar, Azra Frkatovic, Sodbo Sharapov, Qinchuan Wang, Heather Neu, Xinqun Wu, Talin Haritunians, Fengyi Wan, Sarah L. J. Michel, Shaoguang Wu, Dermot McGovern, Gordan Lauc, Mark Donowitz, Cynthia L. Sears, Joanna M.P. Melia
Identification of MHC class I bound peptides by immunopurification of MHC complexes and subsequent analysis by mass spectrometry is crucial for understanding T cell immunology and immunotherapy. Investigation of the steps for the MHC ligand isolation process revealed biases in widely used isolation techniques towards peptides of lower hydrophobicity. As MHC ligand hydrophobicity correlates positively with immunogenicity, identification of more hydrophobic MHC ligands could potentially lead to more effective isolation of immunogenic peptides as targets for immunotherapies. We solved this problem by use of higher concentrations of acetonitrile (ACN) for the separation of MHC ligands and their respective complexes. This increased overall MHC ligand identifications by 2-fold, detection of cancer germline antigen-derived peptides by 50%, and resulted in profound variations in isolation efficacy between different MHC alleles correlating with the hydrophobicity of their anchor residues. Overall, these insights enabled a more complete view on the immunopeptidome and overcame a systematic underrepresentation of these critical MHC ligands of high hydrophobicity.
Martin G. Klatt, Kyeara N. Mack, Yang Bai, Zita E.H. Aretz, Levy I. Nathan, Sung Soo Mun, Tao Dao, David A. Scheinberg
Huntington’s disease (HD) is a progressive autosomal dominant neurodegenerative disorder affecting striatal neurons beginning in young adults with loss of muscle coordination and cognitive decline. Less appreciated is the fact that HD patients also exhibit cardiac and respiratory dysfunction including pulmonary insufficiency and cardiac arrhythmias. The underlying mechanism for these symptoms is poorly understood. In the present study we provide insight into the cause of cardiorespiratory dysfunction in HD and identify a novel therapeutic target. We now show that intracellular calcium (Ca2+) leak via post-translationally modified ryanodine receptor/intracellular calcium release (RyR) channels plays an important role in HD pathology. RyR channels were oxidized, PKA phosphorylated and leaky in brain, heart and diaphragm in both HD patients and in a murine model of HD (Q175). HD mice (Q175) with endoplasmic reticulum (ER) Ca2+ leak exhibited cognitive dysfunction, decreased parasympathetic tone associated with cardiac arrhythmias, and reduced diaphragmatic contractile function resulting in impaired respiratory function. Defects in cognitive, motor and respiratory functions were ameliorated by treatment with a novel Rycal small molecule drug (S107) that fixes leaky RyR. Thus, leaky RyRs likely play a role in neuronal, cardiac and diaphragmatic pathophysiology in HD and identify RyRs as a potential novel therapeutic target.
Haikel Dridi, Xiaoping Liu, Qi Yuan, Steve Reiken, Yehya Mohamad, Leah R. Sittenfeld, Panagiota Apostolou, Julie Buron, Pierre Sicard, Stefan Matecki, Jérôme Thireau, Clement Menuet, Alain Lacampagne, Andrew R. Marks
In aging mice, osteoclast number increases in cortical bone but declines in trabecular bone, suggesting that different mechanisms underlie age-associated bone loss in these two compartments. Osteocytes produce the osteoclastogenic cytokine RANKL, encoded by Tnfsf11. Tnfsf11 mRNA increases in cortical bone of aged mice, suggesting a mechanism underlying the bone loss. To address this possibility, we aged mice lacking RANKL in osteocytes. Whereas 24-month-old control mice had lower cortical bone compared to 8-month-old controls, mice lacking RANKL in osteocytes gained cortical bone from 8 to 24 months of age. Mice of both genotypes lost trabecular bone with age. Osteoclasts increased with age in cortical bone of control mice, but not in RANKL conditional knockout mice. Induction of cellular senescence increased RANKL production in murine and human cell culture models, suggesting an explanation for elevated RANKL levels with age. Over-expression of the senescence-associated transcription factor Gata4 stimulated Tnfsf11 expression in cultured murine osteoblastic cells. Lastly, elimination of senescent cells from aged mice using senolytic compounds reduced Tnfsf11 mRNA in cortical bone. Our results demonstrate the requirement of osteocyte-derived RANKL for age-associated cortical bone loss and suggest that increased Tnfsf11 expression with age results from accumulation of senescent cells in cortical bone.
Ha-Neui Kim, Jinhu Xiong, Ryan S. MacLeod, Srividhya Iyer, Yuko Fujiwara, Keisha M. Cawley, Li Han, Yonghan He, Jeff D. Thostenson, Elisabeth Ferreira, Robert L. Jilka, Daohong Zhou, Maria Almeida, Charles A. O'Brien
Lupus Nephritis (LN) is a major organ complication and cause of morbidity and mortality in patients with systemic lupus erythematosus (SLE). There is an unmet medical need for developing more efficient and specific, mechanism-based therapies, which depends on improved understanding of the underlying LN pathogenesis. Here we present direct visual evidence from high-power intravital imaging of the local kidney tissue microenvironment in new mouse models showing that activated memory T cells originated in immune organs and the LN-specific robust accumulation of the glomerular endothelial glycocalyx play central roles in LN development. The glomerular homing of T cells was mediated via the direct binding of their CD44 to the hyaluronic acid (HA) component of the endothelial glycocalyx, and glycocalyx-degrading enzymes efficiently disrupted it. Short-course treatment with either hyaluronidase or heparinase III provided long-term organ protection as evidenced by vastly improved albuminuria and survival rate. This glycocalyx/HA/memory T cell interaction is present in multiple SLE-affected organs, and may be therapeutically targeted for SLE complications including LN.
Hiroyuki Kadoya, Ning Yu, Ina Maria Schiessl, Anne Riquier-Brison, Georgina Gyarmati, Dorinne Desposito, Kengo Kidokoro, Matthew J. Butler, Chaim O. Jacob, János Peti-Peterdi
The Ca2+-binding protein calmodulin has emerged as a pivotal player in tuning Na+ channel function, although its impact in vivo remains to be resolved. Here, we identify the role of calmodulin and the NaV1.5 interactome in regulating late Na+ current in cardiomyocytes. We created transgenic mice with cardiac-specific expression of human NaV1.5 channels with alanine-substitutions for the IQ motif (IQ/AA). The mutations rendered the channels incapable of binding calmodulin to the C-terminus. The IQ/AA transgenic mice exhibited normal ventricular repolarization without arrhythmias, and an absence of increased late Na+ current. In comparison, transgenic mice expressing a lidocaine-resistant (F1759A) human NaV1.5 demonstrated increased late Na+ current and prolonged repolarization in cardiomyocytes, with spontaneous arrhythmias. To determine regulatory factors that prevent late Na+ current for IQ/AA mutant, we considered fibroblast growth factor homologous factors (FHFs), which are within the NaV1.5 proteomic subdomain shown by proximity labeling in transgenic mice expressing NaV1.5 conjugated to ascorbate peroxidase. We find FGF13 diminishes late current of the IQ/AA but not F1759A mutant cardiomyocytes, suggesting that endogenous FHFs may serve to prevent late Na+ current in mouse cardiomyocytes. Leveraging endogenous mechanisms may furnish an alternative avenue for developing novel pharmacology that selectively blunts late Na+ current.
Jeffrey M. Abrams, Daniel Roybal, Nourdine Chakouri, Alex N. Katchman, Richard L. Weinberg, Lin Yang, Bi-Xing Chen, Sergey I. Zakharov, Jessica A. Hennessey, Uma Mahesh R. Avula, Johanna Diaz, Chaojian Wang, Elaine Y. Wan, Geoffrey S. Pitt, Manu Ben-Johny, Steven O. Marx
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