Abstract
This study examined the involvement of fibroblast growth factor-23 (FGF-23) in primary aldosteronism (PA), a condition characterized by elevated aldosterone levels and hypertension. We recruited patients with unilateral PA (uPA) and observed increased levels of C-terminal FGF-23 (cFGF-23) and C-terminal to intact FGF-23 (iFGF-23) in patients with uPA compared with essential hypertension control participants. Elevated preoperative cFGF-23 levels were associated with adverse outcomes, including mortality and cardiovascular or kidney events. Plasma cFGF-23 levels demonstrated a nonlinear rise with aldosterone, but iFGF-23 levels were not correlated with plasma aldosterone concentration. Higher cFGF-23 levels independently predicted hypertension remission after adrenalectomy for patients with uPA. Patients with uPA, who exhibited elevated cFGF-23 levels, had decreased levels after adrenalectomy. In cell cultures, aldosterone enhanced cleavage of iFGF-23, leading to increased levels of cFGF-23 fragments, an effect mitigated by silencing of family with sequence similarity 20, member C (FAM20C). However, the enhancement of cFGF-23 levels remained unaffected by the furin inhibitor. The study suggests that aldosterone influences FGF-23 phosphorylation by interacting with FAM20C, with docking experiments indicating aldosterone’s binding to FAM20C. This work highlights that patients with uPA with elevated cFGF-23 levels are associated with cardiovascular risks, and adrenalectomy reduces cFGF-23. Aldosterone likely promotes cFGF-23 production through FAM20C-mediated phosphorylation of iFGF-23.
Authors
Vin-Cent Wu, Kang-Yung Peng, Tsu-I Chen, Chiao-Yin Sun, Hung-Wei Liao, Chieh-Kai Chan, Yen-Hung Lin, Hung-Hsiang Liou, Jeff S. Chueh
Abstract
Aortic dissection or rupture is a major cause of mortality in vascular Ehlers-Danlos Syndrome (vEDS), a connective tissue disorder caused by heterozygous mutations in the COL3A1 gene. C57BL6/J (BL6) mice carrying the Col3a1 G938D/+ mutation recapitulate the vEDS vascular phenotype and die suddenly of aortic rupture/dissection. However, 129S6/SvEvTac (129) mice expressing the same Col3a1 G938D/+ mutation show near-complete life-long protection from vascular rupture. To identify genetic modifiers of vascular risk in vEDS, we performed genome-wide genotyping of intercrossed BL6/129 vEDS mice stratified by survival and identified a significant protective locus encompassing a variant in Map2k6, encoding Mitogen-Activated Protein Kinase Kinase 6 (M2K6), a p38-activating kinase. Genetic ablation of Map2k6 rendered previously protected 129 vEDS mice susceptible to aortic rupture, in association with reduced protein phosphatase 1 activity and increased PKC and ERK phosphorylation. Accelerated vascular rupture in vEDS mice treated with a pharmacological inhibitor of p38 was rescued by concomitant ERK antagonism, supporting an opposing role for ERK and p38 in the modification of aortic rupture risk in vEDS. These results suggest that pharmacologic strategies aimed at mimicking the effect of this natural protective pathway may improve prevention of aortic rupture risk in vEDS.
Authors
Caitlin J. Bowen, Rebecca Sorber, Juan F. Calderon Giadrosic, Jefferson J. Doyle, Graham Rykiel, Zachary Burger, Xiaoyan Zhang, Wendy A. Espinoza Camejo, Nicole K. Anderson, Simone Sabnis, Chiara Bellini, Elena MacFarlane, Harry C. Dietz
Abstract
The hERG1 potassium channel conducts the cardiac repolarizing current, IKr. hERG1 has emerged as a therapeutic target for cardiac diseases marked by prolonged actional potential duration (APD). Unfortunately, many hERG1 activators display off-target and proarrhythmic effects that limit their therapeutic potential. A Per-Arnt-Sim (PAS) domain in the hERG1 N-terminus reduces IKr by slowing channel activation and promoting inactivation. Disrupting PAS activity increases IKr and shortens APD in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). We thus hypothesized that the hERG1 PAS domain could represent a therapeutic target to reduce arrhythmogenic potential in a long QT syndrome (LQTS) background. To test this, we measured the antiarrhythmic capacity of a PAS-disabling single-chain variable fragment antibody, scFv2.10, in a hiPSC-CM line derived from a Jervell and Lange Nielsen syndrome (JLN) patient. JLN is a severe form of LQTS caused by autosomal recessive mutations in KCNQ1. The patient in this study carried compound heterozygous mutations in KCNQ1. Corresponding JLN hiPSC-CMs displayed prolonged APD and early after depolarizations (EADs). Disrupting PAS with scFv2.10 increased IKr, shortened APD, and reduced the incidence of EADs. These data demonstrate that the hERG1 PAS domain could serve as a therapeutic target to treat disorders of cardiac electrical dysfunction.
Authors
Chiamaka U. Ukachukwu, Eric N. Jimenez-Vazquez, Shreya Salwi, Matthew Goodrich, Francisco G. Sanchez-Conde, Kate M. Orland, Abhilasha Jain, Lee L. Eckhardt, Timothy J. Kamp, David K. Jones
Abstract
African American (AA) women are disproportionally affected by obesity and hyperlipidemia, particularly in the setting of adverse social determinants of health (aSDoH) contributing to health disparities. Obesity, hyperlipidemia, and aSDoH appear to impair Natural Killer cells (NKs). As potential common underlying mechanisms are largely unknown, we sought to investigate common signaling pathways involved in NK dysfunction related to obesity and hyperlipidemia in AA women from under-resourced neighborhoods. We determined in freshly isolated NKs that obesity and measures of aSDoH are associated with a shift in NK subsets away from CD56dim/CD16+ cytotoxic NKs. Using ex vivo data, we identified LDL as a marker related to NK cell function in an AA population from under-resourced neighborhoods. Additionally, NK cells from AA women with obesity and LDL-treated NK cells displayed a loss in NK cell function. Comparative unbiased RNA sequencing analysis revealed DUSP1 as a common factor. Subsequently, chemical inhibition of DUSP1 and DUSP1 overexpression in NK cells highlighted its significance in NK cell function and lysosome biogenesis in a mTOR/TFEB-related fashion. Our data demonstrate a pathway by which obesity and hyperlipidemia in the setting of aSDoH may relate to NK dysfunction, making DUSP1 an important target for further investigation of health disparities.
Authors
Yvonne Baumer, Komudi Singh, Abhinav Saurabh, Andrew S. Baez, Cristhian A. Gutierrez-Huerta, Long Chen, Muna Igboko, Briana S. Turner, Josette A. Yeboah, Robert N. Reger, Lola R. Ortiz-Whittingham, Sahil Joshi, Marcus R. Andrews, Elizabeth M. Aquino Peterson, Christopher K.E. Bleck, Laurel G. Mendelsohn, Valerie M. Mitchell, Billy S. Collins, Neelam R. Redekar, Skyler A. Kuhn, Christian A. Combs, Mehdi Pirooznia, Pradeep K. Dagur, David S.J. Allan, Daniella Muallem-Schwartz, Richard W. Childs, Tiffany M. Powell-Wiley
Abstract
BACKGROUND Sodium-glucose cotransporter 2 inhibitors slow down progression of chronic kidney disease (CKD). We tested whether the circulating substrate mix is related to CKD progression and cardiovascular outcomes in patients with type 2 diabetes (T2D) and albuminuric CKD in the CREDENCE trial.METHODS We measured fasting substrates in 2,543 plasma samples at baseline and 1 year after randomization to either 100 mg canagliflozin or placebo and used multivariate Cox models to explore their association with CKD progression, heart failure hospitalization/cardiovascular death (hHF/CVD), and mortality.RESULTS Higher baseline lactate and free fatty acids (FFAs) were independently associated with a lower risk of CKD progression (HR = 0.73 [95% CI: 0.54–0.98] and HR = 0.67 [95% CI: 0.48–0.95], respectively) and hHF/CVD HR = 0.70 [95% CI: 0.50–0.99] and HR = 0.63 [95% CI: 0.42–0.94]). Canagliflozin led to a rise in plasma FFAs, glycerol, β-hydroxybutyrate, and acetoacetate. Changes in substrate between baseline and year 1 predicted an approximately 30% reduction in relative risk of both CKD progression and hHF/CVD independently of treatment. More patients who did not respond to canagliflozin treatment in terms of CKD progression belonged to the bottom lactate and FFA distribution tertiles.CONCLUSION In T2D patients with albuminuric CKD, basic energy substrates selectively influenced major long-term endpoints; canagliflozin treatment amplified their effects by chronically raising their circulating levels.
Authors
Ele Ferrannini, Simona Baldi, Maria Tiziana Scozzaro, Giulia Ferrannini, Michael K. Hansen
Insulin mitigates acute ischemia induced atrial fibrillation and sinoatrial node dysfunction ex vivo
Abstract
Acute atrial ischemia is a well-known cause of postoperative atrial fibrillation (POAF). However, mechanisms through which ischemia contributes to the development of POAF are not well understood. In this study, ex vivo Langendorff perfusion was used to induce acute ischemia and reperfusion in the heart in order to mimic POAF. Inducibility of atrial fibrillation (AF) was evaluated using programmed electrical stimulation and confirmed with open-atrium optical mapping. Compared to the control group without ischemia, 25 minutes of ischemia substantially increased the incidence of AF. The right atrium was more susceptible to AF than the left atrium. Administering insulin for 30 minutes before ischemia and during reperfusion with 25 minutes of ischemia greatly reduced the vulnerability to AF. However, insulin treatment during reperfusion only did not show substantial benefits against AF. Optical mapping studies showed that insulin mitigates ischemia-induced abnormal electrophysiology, including shortened action potential duration and effective refractory period, slowed conduction velocity, increased conduction heterogeneity, and altered calcium transients. In conclusion, insulin reduced the risk of acute ischemia/reperfusion-induced AF via improving the electrophysiology and calcium handling of atrial cardiomyocytes, which provides a potential therapy for POAF.
Authors
Huiliang Qiu, Fan Li, Hannah Prachyl, Alejandra Patino-Guerrero, Michael Rubart, Wuqiang Zhu
Abstract
Congenital heart disease (CHD) affects ~1% of live births. Although genetic and environmental etiologic contributors have been identified, the majority of CHD lacks a definitive cause, suggesting the role of gene-environment interactions (GxE) in disease pathogenesis. Maternal diabetes mellitus (matDM) is among the most prevalent environmental risk factors for CHD. However, there is a substantial knowledge gap in understanding how matDM acts upon susceptible genetic backgrounds to increase disease expressivity. Previously, we reported a GxE between Notch1 haploinsufficiency and matDM leading to increased CHD penetrance. Here, we demonstrate a cell lineage specific effect of Notch1 haploinsufficiency in matDM-exposed embryos, implicating endothelial/endocardial derived tissues in the developing heart. We report impaired atrioventricular cushion morphogenesis in matDM exposed Notch1+/- animals and show a synergistic effect of NOTCH1 haploinsufficiency and oxidative stress in dysregulation of gene regulatory networks critical for endocardial cushion morphogenesis in vitro. Mitigation of matDM-associated oxidative stress via SOD1 overexpression did not rescue CHD in Notch1 haploinsufficient mice compared to wildtype littermates. Our results show the combinatorial interaction of matDM-associated oxidative stress and a genetic predisposition, Notch1 haploinsufficiency, on cardiac development, supporting a GxE model for CHD etiology and suggesting that antioxidant strategies maybe ineffective in genetically-susceptible individuals.
Authors
Talita Z. Choudhury, Sarah C. Greskovich, Holly B. Girard, Anupama S. Rao, Yogesh Budhathoki, Emily M. Cameron, Sara Conroy, Deqiang Li, Ming-Tao Zhao, Vidu Garg
Abstract
Lipoprotein lipase (LPL) and multiple regulators of LPL activity (e.g., APOC2 and ANGPTL4) are present in all vertebrates, but GPIHBP1—the endothelial cell (EC) protein that captures LPL within the subendothelial spaces and transports it to its site of action in the capillary lumen—is present in mammals but in not chickens or other lower vertebrates. In mammals, GPIHBP1 deficiency causes severe hypertriglyceridemia, but chickens maintain low triglyceride levels despite the absence of GPIHBP1. To understand intravascular lipolysis in lower vertebrates, we examined LPL expression in mouse and chicken hearts. In both species, LPL was abundant on capillaries, but the distribution of Lpl transcripts was strikingly different. In mouse hearts, Lpl transcripts were extremely abundant in cardiomyocytes but were barely detectable in capillary ECs. In chicken hearts, Lpl transcripts were absent in cardiomyocytes but abundant in capillary ECs. In zebrafish hearts, lpl transcripts were also in capillary ECs but not cardiomyocytes. In both mouse and chicken hearts, LPL was present, as judged by immunogold electron microscopy, in the glycocalyx of capillary ECs. Thus, mammals produce LPL in cardiomyocytes and rely on GPIHBP1 to transport the LPL into capillaries, whereas lower vertebrates produce LPL directly in capillary ECs, rendering an LPL transporter unnecessary.
Authors
Le Phuong Nguyen, Wenxin Song, Ye Yang, Anh P. Tran, Thomas A. Weston, Hyesoo Jung, Yiping Tu, Paul H. Kim, Joonyoung R. Kim, Katherine Xie, Rachel G. Yu, Julia Scheithauer, Ashley M. Presnell, Michael Ploug, Gabriel Birrane, Hannah Arnold, Katarzyna Koltowska, Maarja A. Mäe, Christer Betsholtz, Liqun He, Jeffrey L. Goodwin, Anne P. Beigneux, Loren G. Fong, Stephen G. Young
Abstract
Left ventricular hypertrophy (LVH) and dyslipidemia are strong, independent predictors for cardiovascular disease, but their relationship is less well-studied. A longitudinal lipidomic profiling of left ventricular mass (LVM) and LVH is still lacking. Using LC-MS, we repeatedly measured 1,542 lipids from 1,755 unique American Indians attending two exams (mean~5-year apart). Cross-sectional associations of individual lipid species with LVM index (LVMI) were examined by generalized estimating equation (GEE), followed by replication in an independent bi-racial cohort (65% white, 35% black). Baseline plasma lipids associated with LVH risk beyond traditional risk factors were identified by Cox frailty model in American Indians. Longitudinal associations between changes in lipids and changes in LVMI were examined by GEE, adjusting for baseline lipids, baseline LVMI, and covariates. Multiple lipid species (e.g., glycerophospholipids, sphingomyelins, acylcarnitines) were significantly associated with LVMI or the risk of LVH in American Indians. Some lipids were confirmed in black and white individuals. Moreover, some LVH-related lipids were inversely associated with risk of coronary heart disease (CHD). Longitudinal changes in several lipid species (e.g., glycerophospholipids, sphingomyelins, cholesterol esters) were significantly associated with changes in LVMI. These findings provide insights into the role of lipid metabolism in LV remodeling and the risk of LVH or CHD.
Authors
Mingjing Chen, Zhijie Huang, Guanhong Miao, Jin Ren, Jinling Liu, Mary J. Roman, Richard B. Devereux, Richard R. Fabsitz, Ying Zhang, Jason G. Umans, Shelley A. Cole, Tanika N. Kelly, Oliver Fiehn, Jinying Zhao
Abstract
Chronic activation of the adaptive immune system is a hallmark of atherosclerosis. As PI3Kδ is a key regulator of T and B-cell differentiation and function, we hypothesized that alleviation of adaptive immunity by PI3Kδ inactivation may represent an attractive strategy counteracting atherogenesis. As expected, lack of hematopoietic PI3Kδ in atherosclerosis-prone Ldlr–/– mice resulted in hindered T- and B-cell numbers, CD4+ effector T cells, Th1 response, and immunoglobulin levels. However, despite markedly impaired peripheral proinflammatory Th1 cells and atheromatous CD4+ T cells, the unexpected net effect of hematopoietic PI3Kδ deficiency was aggravated vascular inflammation and atherosclerosis. Further analyses revealed that PI3Kδ deficiency impaired numbers, immunosuppressive functions, and stability of regulatory CD4+ T cells (Tregs), whereas macrophage biology remained largely unaffected. Adoptive transfer of wild-type Tregs fully restrained the atherosclerotic plaque burden in Ldlr–/– mice lacking hematopoietic PI3Kδ, whereas PI3Kδ deficient Tregs failed to mitigate disease. Numbers of atheroprotective B-1 and proatherogenic B-2 cells as well serum immunoglobulin levels remained unaffected by adoptively transferred wild-type Tregs. In conclusion, we demonstrate that hematopoietic PI3Kδ ablation promotes atherosclerosis. Mechanistically, we identified PI3Kδ signaling as a powerful driver of atheroprotective Treg responses, which outweigh PI3Kδ driven proatherogenic effects of adaptive immune cells like Th1 cells.
Authors
Mario Zierden, Eva Maria Berghausen, Leoni Gnatzy-Feik, Christopher Millarg, Felix Simon Ruben Picard, Martha Kiljan, Simon Geißen, Apostolos Polykratis, Lea Zimmermann, Richard Julius Nies, Manolis Pasparakis, Stephan Baldus, Chanil Valasarajan, Soni Savai Pullamsetti, Holger Winkels, Marius Vantler, Stephan Rosenkranz
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