Publications by authors named "Robert M Weiss"

151 Publications

Counterpoint regarding an alternative hypothesis for why exposure to static magnetic and electric fields treat type 2 diabetes.

Am J Physiol Endocrinol Metab 2021 Apr 12. Epub 2021 Apr 12.

Radiation Oncology, Univerisity of Iowa.

Petersen et al. hypothesize that vestibular stress underlies the therapeutic effects of static magnetic and electric fields in type 2 diabetes. However, our experimental data directly contradict the predictions made by this alternative hypothesis. Here, we discuss key findings that support a mechanism that is independent of vestibular stress to explain the remarkable insulin sensitizing effects of static magnetic and electric fields. Our findings are consistent with a redox-dependent mechanism that involves mitochondrial oxidants in liver and the induction of an insulin sensitizing redox response.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1152/ajpendo.00110.2021DOI Listing
April 2021

Genome-wide association analysis reveals regulation of at-risk loci by DNA methylation in prostate cancer.

Asian J Androl 2021 Mar 23. Epub 2021 Mar 23.

Department of Urology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China.

Epigenetic changes are potentially important for the ontogeny and progression of tumors but are not usually studied because of the complexity of analyzing transcript regulation resulting from epigenetic alterations. Prostate cancer (PCa) is characterized by variable clinical manifestations and frequently unpredictable outcomes. We performed an expression quantitative trait loci (eQTL) analysis to identify the genomic regions that regulate gene expression in PCa and identified a relationship between DNA methylation and clinical information. Using multi-level information published in The Cancer Genome Atlas, we performed eQTL-based analyses on DNA methylation and gene expression. To better interpret these data, we correlated loci and clinical indexes to identify the important loci for both PCa development and progression. Our data demonstrated that although only a small proportion of genes are regulated via DNA methylation in PCa, these genes are enriched in important cancer-related groups. In addition, single nucleotide polymorphism analysis identified the locations of CpG sites and genes within at-risk loci, including the 19q13.2-q13.43 and 16q22.2-q23.1 loci. Further, an epigenetic association study of clinical indexes detected risk loci and pyrosequencing for site validation. Although DNA methylation-regulated genes across PCa samples are a small proportion, the associated genes play important roles in PCa carcinogenesis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4103/aja.aja_20_21DOI Listing
March 2021

Achieving highly efficient gene transfer to the bladder by increasing the molecular weight of polymer-based nanoparticles.

J Control Release 2021 Apr 17;332:210-224. Epub 2021 Feb 17.

School of Pharmacy, University College London, London, UK. Electronic address:

Short dwell-time and poor penetration of the bladder permeability barrier (BPB) are the main obstacles to intravesical treatments for bladder diseases, and is evidenced by the lack of such therapeutic options on the market. Herein, we demonstrate that by finely tuning the molecular weight of our cationic polymer mucoadhesive nanoparticles, we enhanced our gene transfer, leading to improved adherence and penetrance through the BPB in a safe and efficient manner. Specifically, increasing the polymer molecular weight from 45 kDa to 83 kDa enhanced luciferase plasmid transfer to the healthy murine bladder, leading to 1.35 ng/g luciferase protein expression in the urothelium and lamina propria regions. The relatively higher molecular weight polymer (83 kDa) did not induce morphologic changes or inflammatory responses in the bladder. This approach of altering polymer molecular weight for prolonging gene transfer residence time and deeper penetration through the BPB could be the basis for the design of future gene therapies for bladder diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jconrel.2021.02.007DOI Listing
April 2021

Tumor necrosis factor-α promotes and exacerbates calcification in heart valve myofibroblast populations.

FASEB J 2021 Mar;35(3):e21382

Department of Chemical and Biological Engineering, University of Colorado Boulder, Boulder, CO, USA.

Pro-inflammatory cytokines play critical roles in regulating valvular interstitial cell (VIC) phenotypic changes that can cause heart valve fibrosis and calcification. Tumor necrosis factor alpha (TNF-α) is a cytokine known to influence VIC behavior and has been reported at high levels in calcified valves ex vivo. We sought to understand the specific effects of TNF-α on VIC phenotypes (eg, fibroblast, profibrotic activated myofibroblasts) and its link with heart valve disorders. We characterize human aortic valve tissue from patients with valve disorders and identify a high variability of fibrotic and calcific markers between tissues. These results motivated in vitro studies to explore the effects of TNF-α on defined VIC fibroblasts and profibrotic activated myofibroblasts, induced via FGF-2 and TGF-β1 treatment. Using 3D hydrogels to culture VICs, we measure the effect of TNF-α (0.1-10 ng/mL) on key markers of fibrosis (eg, αSMA, COL1A1) and calcification (eg, RUNX2, BMP2, and calcium deposits). We observe calcification in TNF-α-treated VIC activated myofibroblasts and identify the MAPK/ERK signaling cascade as a potential pathway for TNF-α mediated calcification. Conversely, VIC fibroblasts respond to TNF-α with decreased calcification. Treatment of VIC profibrotic activated myofibroblast populations with TNF-α leads to increased calcification. Our in vitro findings correlate with findings in diseased human valves and highlight the importance of understanding the effect of cytokines and signaling pathways on specific VIC phenotypes. Finally, we reveal MAPK/ERK as a potential pathway involved in VIC-mediated matrix calcification with TNF-α treatment, suggesting this pathway as a potential pharmaceutical target for aortic valve disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1096/fj.202002013RRDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7875331PMC
March 2021

Silencing Epidermal Growth Factor Receptor in Hypothalamic Paraventricular Nucleus Reduces Extracellular Signal-regulated Kinase 1 and 2 Signaling and Sympathetic Excitation in Heart Failure Rats.

Neuroscience 2021 May 2;463:227-237. Epub 2021 Feb 2.

Department of Internal Medicine, Roy J and Lucille A Carver College of Medicine, University of Iowa, Iowa City, IA, USA; VA Medical Center, Iowa City, IA, USA. Electronic address:

Activation of extracellular signal-regulated kinase 1 and 2 (ERK1/2) signaling in cardiovascular regulatory regions of the brain contributes to sympathetic excitation in myocardial infarction (MI)-induced heart failure (HF) by increasing brain renin-angiotensin system (RAS) activity, neuroinflammation, and endoplasmic reticulum (ER) stress. The mechanisms eliciting brain ERK1/2 signaling in HF are still poorly understood. We tested the involvement of the epidermal growth factor receptor (EGFR) which, upon activation, stimulates ERK1/2 activity. Adult male Sprague-Dawley rats received bilateral microinjections of a lentiviral vector encoding a small interfering RNA (siRNA) for EGFR, or a scrambled siRNA, into the hypothalamic paraventricular nucleus (PVN), a recognized source of sympathetic overactivity in HF. One week later, coronary artery ligation was performed to induce HF. Four weeks later, the EGFR siRNA-treated HF rats, compared with the scrambled siRNA-treated HF rats, had lower mRNA and protein levels of EGFR, lower levels of phosphorylated (p-) EGFR and p-ERK1/2 and lower mRNA levels of the inflammatory mediators TNF-α, IL-1β and cyclooxygenase-2, the RAS components angiotensin-converting enzyme and angiotensin II type 1a receptor and the ER stress markers BIP and ATF4 in the PVN. They also had lower plasma and urinary norepinephrine levels and improved peripheral manifestations of HF. Additional studies revealed that p-EGFR was increased in the PVN of HF rats, compared with sham-operated control rats. These results suggest that activation of EGFR in the PVN triggers ERK1/2 signaling, along with ER stress, neuroinflammation and RAS activity, in MI-induced HF. Brain EGFR may be a novel target for therapeutic intervention in MI-induced HF.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.neuroscience.2021.01.025DOI Listing
May 2021

Down-regulation of GP130 signaling sensitizes bladder cancer to cisplatin by impairing Ku70 DNA repair signaling and promoting apoptosis.

Cell Signal 2021 May 30;81:109931. Epub 2021 Jan 30.

Department of Urology, Yale University, New Haven, CT, USA. Electronic address:

Chemoresistance is one of the barriers for the development of bladder cancer treatments. Previously, we showed that glycoprotein-130 (GP130) is overexpressed in chemoresistant bladder cancer cells and that knocking down GP130 expression reduced cell viability. In our current work, we showed that down-regulation of GP130 sensitized bladder cancer cells to cisplatin-based chemotherapy by activating DNA repair signaling. We performed immunohistochemistry and demonstrated a positive correlation between the levels of Ku70, an initiator of canonical non-homologous end joining repair (c-NHEJ) and suppressor of apoptosis, and GP130 in human bladder cancer specimens. GP130 knockdown by SC144, a small molecule inhibitor, in combination with cisplatin, increased the number of DNA lesions, specifically DNA double-stranded breaks, with a subsequent increase in apoptosis and reduced cell viability. Furthermore, GP130 inhibition attenuated Ku70 expression in bladder and breast cancer cells as well as in transformed kidney cells. In addition, we fabricated a novel polymer-lipid hybrid delivery system to facilitate GP130 siRNA delivery that had a similar efficiency when compared with Lipofectamine, but induced less toxicity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cellsig.2021.109931DOI Listing
May 2021

Collagen networks within 3D PEG hydrogels support valvular interstitial cell matrix mineralization.

Acta Biomater 2021 01 9;119:197-210. Epub 2020 Nov 9.

Materials Science and Engineering Program, University of Colorado Boulder, 3415 Colorado Avenue, Boulder CO 80303, USA; Department of Chemical and Biological Engineering, University of Colorado Boulder, 3415 Colorado Avenue, Boulder CO 80303, USA; The BioFrontiers Institute, University of Colorado Boulder, 3415 Colorado Avenue, Boulder CO 80303, USA. Electronic address:

Enzymatically degradable hydrogels were designed for the 3D culture of valvular interstitial cells (VICs), and through the incorporation of various functionalities, we aimed to investigate the role of the tissue microenvironment in promoting the osteogenic properties of VICs and matrix mineralization. Specifically, porcine VICs were encapsulated in a poly(ethylene glycol) hydrogel crosslinked with a matrix metalloproteinase (MMP)-degradable crosslinker (KCGPQG↓IWGQCK) and formed via a thiol-ene photoclick reaction in the presence or absence of collagen type I to promote matrix mineralization. VIC-laden hydrogels were treated with osteogenic medium for up to 15 days, and the osteogenic response was characterized by the expression of RUNX2 as an early marker of an osteoblast-like phenotype, osteocalcin (OCN) as a marker of a mature osteoblast-like phenotype, and vimentin (VIM) as a marker of the fibroblast phenotype. In addition, matrix mineralization was characterized histologically with Von Kossa stain for calcium phosphate. Osteogenic response was further characterized biochemically with calcium assays, and physically via optical density measurements. When the osteogenic medium was supplemented with calcium chloride, OCN expression was upregulated and mineralization was discernable at 12 days of culture. Finally, this platform was used to screen various drug therapeutics that were assessed for their efficacy in preventing mineralization using optical density as a higher throughput readout. Collectively, these results suggest that matrix composition has a key role in supporting mineralization deposition within diseased valve tissue.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.actbio.2020.11.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7738375PMC
January 2021

Mitochondrial pyruvate carriers are required for myocardial stress adaptation.

Nat Metab 2020 11 26;2(11):1248-1264. Epub 2020 Oct 26.

Fraternal Order of Eagles Diabetes Research Center, Carver College of Medicine, University of Iowa, Iowa City, IA, USA.

In addition to fatty acids, glucose and lactate are important myocardial substrates under physiologic and stress conditions. They are metabolized to pyruvate, which enters mitochondria via the mitochondrial pyruvate carrier (MPC) for citric acid cycle metabolism. In the present study, we show that MPC-mediated mitochondrial pyruvate utilization is essential for the partitioning of glucose-derived cytosolic metabolic intermediates, which modulate myocardial stress adaptation. Mice with cardiomyocyte-restricted deletion of subunit 1 of MPC (cMPC1) developed age-dependent pathologic cardiac hypertrophy, transitioning to a dilated cardiomyopathy and premature death. Hypertrophied hearts accumulated lactate, pyruvate and glycogen, and displayed increased protein O-linked N-acetylglucosamine, which was prevented by increasing availability of non-glucose substrates in vivo by a ketogenic diet (KD) or a high-fat diet, which reversed the structural, metabolic and functional remodelling of non-stressed cMPC1 hearts. Although concurrent short-term KDs did not rescue cMPC1 hearts from rapid decompensation and early mortality after pressure overload, 3 weeks of a KD before transverse aortic constriction was sufficient to rescue this phenotype. Together, our results highlight the centrality of pyruvate metabolism to myocardial metabolism and function.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s42255-020-00288-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8015649PMC
November 2020

Secreted Factors From Proinflammatory Macrophages Promote an Osteoblast-Like Phenotype in Valvular Interstitial Cells.

Arterioscler Thromb Vasc Biol 2020 11 17;40(11):e296-e308. Epub 2020 Sep 17.

Department of Chemical and Biological Engineering (J.C.G., B.A.A., B.J.V., C.L.A., A.G.-R., F.M.Y., K.S.A.), University of Colorado Boulder, Boulder.

Objective: Resident valvular interstitial cells (VICs) activate to myofibroblasts during aortic valve stenosis progression, which further promotes fibrosis or even differentiate into osteoblast-like cells that can lead to calcification of valve tissue. Inflammation is a hallmark of aortic valve stenosis, so we aimed to determine proinflammatory cytokines secreted from M1 macrophages that give rise to a transient VIC phenotype that leads to calcification of valve tissue. Approach and Results: We designed hydrogel biomaterials as valve extracellular matrix mimics enabling the culture of VICs in either their quiescent fibroblast or activated myofibroblast phenotype in response to the local matrix stiffness. When VIC fibroblasts and myofibroblasts were treated with conditioned media from THP-1-derived M1 macrophages, we observed robust reduction of αSMA (alpha smooth muscle actin) expression, reduced stress fiber formation, and increased proliferation, suggesting a potent antifibrotic effect. We further identified TNF (tumor necrosis factor)-α and IL (interleukin)-1β as 2 cytokines in M1 media that cause the observed antifibrotic effect. After 7 days of culture in M1 conditioned media, VICs began differentiating into osteoblast-like cells, as measured by increased expression of RUNX2 (runt-related transcription factor 2) and osteopontin. We also identified and validated IL-6 as a critical mediator of the observed pro-osteogenic effect.

Conclusions: Proinflammatory cytokines in M1 conditioned media inhibit myofibroblast activation in VICs (eg, TNF-α and IL-1β) and promote their osteogenic differentiation (eg, IL-6). Together, our work suggests inflammatory M1 macrophages may drive a myofibroblast-to-osteogenic intermediate VIC phenotype, which may mediate the switch from fibrosis to calcification during aortic valve stenosis progression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/ATVBAHA.120.315261DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7578003PMC
November 2020

Calcium Signaling Regulates Valvular Interstitial Cell Alignment and Myofibroblast Activation in Fast-Relaxing Boronate Hydrogels.

Macromol Biosci 2020 12 13;20(12):e2000268. Epub 2020 Sep 13.

Department of Chemical and Biological Engineering, University of Colorado Boulder, Boulder, CO, 80303, USA.

The role viscoelasticity in fibrotic disease progression is an emerging area of interest. Here, a fast-relaxing hydrogel system is exploited to investigate potential crosstalk between calcium signaling and mechanotransduction. Poly(ethylene glycol) (PEG) hydrogels containing boronate and triazole crosslinkers are synthesized, with varying ratios of boronate to triazole crosslinks to systematically vary the extent of stress relaxation. Valvular interstitial cells (VICs) encapsulated in hydrogels with the highest levels of stress relaxation (90%) exhibit a spread morphology by day 1 and are highly aligned (80 ± 2%) by day 5. Key myofibroblast markers, including α-smooth muscle actin (αSMA) and collagen 1a1 (COL1A1), are significantly elevated. VIC myofibroblast activation decreases by 42 ± 18% through inhibition of mechanotransduction, independently of VIC morphology and alignment. Calcium signaling through a transient receptor potential vanilloid 4 (TRPV4) is found to regulate VIC spreading, alignment, and activation in a time dependent manner. Inhibition of calcium signaling at early time points results in disturbed cell alignment, decreased mechanotransduction, and diminished activation, while inhibition at later time points only causes partially reduced myofibroblast activation. These results suggest a potential crosstalk mechanism, where calcium signaling acts upstream of mechanosensing and can regulate VIC myofibroblast activation independently of mechanotransduction.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/mabi.202000268DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7773027PMC
December 2020

An Injectable Microparticle Formulation Provides Long-Term Inhibition of Hypothalamic ERK1/2 Activity and Sympathetic Excitation in Rats with Heart Failure.

Mol Pharm 2020 09 4;17(9):3643-3648. Epub 2020 Aug 4.

Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, University of Iowa, Iowa City, Iowa 52242, United States.

Sympathetic excitation contributes to clinical deterioration in systolic heart failure (HF). Significant inhibition of hypothalamic paraventricular nucleus (PVN) ERK1/2 signaling and a subsequent reduction of plasma norepinephrine (NE) levels in HF rats were achieved 2 weeks after a single subcutaneous injection of PD98059-loaded polymeric microparticles, without apparent adverse events, while blank microparticles had no effect. Similar reductions in plasma NE, a general indicator of sympathetic excitation, were previously achieved in HF rats by intracerebroventricular infusion of PD98059 or genetic knockdown of PVN ERK1/2 expression. This study presents a clinically feasible therapeutic approach to the central abnormalities contributing to HF progression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.molpharmaceut.0c00501DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7641013PMC
September 2020

Failure to vasodilate in response to salt loading blunts renal blood flow and causes salt-sensitive hypertension.

Cardiovasc Res 2021 Jan;117(1):308-319

Department of Physiology, Cardiovascular Center, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.

Aims: Salt-sensitive (SS) hypertension is accompanied by impaired vasodilation in the systemic and renal circulation. However, the causal relationship between vascular dysfunction and salt-induced hypertension remains controversial. We sought to determine whether primary vascular dysfunction, characterized by a failure to vasodilate during salt loading, plays a causal role in the pathogenesis of SS hypertension.

Methods And Results: Mice selectively expressing a peroxisome proliferator-activated receptor γ dominant-negative mutation in vascular smooth muscle (S-P467L) exhibited progressive SS hypertension during a 4 week high salt diet (HSD). This was associated with severely impaired vasodilation in systemic and renal vessels. Salt-induced impairment of vasodilation occurred as early as 3 days after HSD, which preceded the onset of SS hypertension. Notably, the overt salt-induced hypertension in S-P467L mice was not driven by higher cardiac output, implying elevations in peripheral vascular resistance. In keeping with this, HSD-fed S-P467L mice exhibited decreased smooth muscle responsiveness to nitric oxide (NO) in systemic vessels. HSD-fed S-P467L mice also exhibited elevated albuminuria and a blunted increase in urinary NO metabolites which was associated with blunted renal blood flow and increased sodium retention mediated by a lack of HSD-induced suppression of NKCC2. Blocking NKCC2 function prevented the salt-induced increase in blood pressure in S-P467L mice.

Conclusion: We conclude that failure to vasodilate in response to salt loading causes SS hypertension by restricting renal perfusion and reducing renal NO through a mechanism involving NKCC2 in a mouse model of vascular peroxisome proliferator-activated receptor γ impairment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/cvr/cvaa147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7797211PMC
January 2021

An injectable microparticle formulation for the sustained release of the specific MEK inhibitor PD98059: in vitro evaluation and pharmacokinetics.

Drug Deliv Transl Res 2021 Feb;11(1):182-191

Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, University of Iowa, Iowa City, IA, 52242, USA.

PD98059 is a reversible MEK inhibitor that we are investigating as a potential treatment for neurochemical changes in the brain that drive neurohumoral excitation in heart failure. In a rat model that closely resembles human heart failure, we found that central administration of PD98059 inhibits phosphorylation of ERK1/2 in the paraventricular nucleus of the hypothalamus, ultimately reducing sympathetic excitation which is a major contributor to clinical deterioration. Studies revealed that the pharmacokinetics and biodistribution of PD98059 match a two-compartment model, with drug found in brain as well as other body tissues, but with a short elimination half-life in plasma (approximately 73 min) that would severely limit its potential clinical usefulness in heart failure. To increase its availability to tissues, we prepared a sustained release PD98059-loaded PLGA microparticle formulation, using an emulsion solvent evaporation technique. The average particle size, yield percent, and encapsulation percent were found to be 16.73 μm, 76.6%, and 43%, respectively. In vitro drug release occurred over 4 weeks, with no noticeable burst release. Following subcutaneous injection of the microparticles in rats, steady plasma levels of PD98059 were detected by HPLC for up to 2 weeks. Furthermore, plasma and brain levels of PD98059 in rats with heart failure were detectable by LC/MS, despite expected erratic absorption. These findings suggest that PD98059-loaded microparticles hold promise as a novel therapeutic intervention countering sympathetic excitation in heart failure, and perhaps in other disease processes, including cancers, in which activated MAPK signaling is a significant contributing factor. Graphical abstract.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s13346-020-00758-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7647946PMC
February 2021

Insulin receptor substrates differentially exacerbate insulin-mediated left ventricular remodeling.

JCI Insight 2020 03 26;5(6). Epub 2020 Mar 26.

Fraternal Order of Eagles Diabetes Research Center and.

Pressure overload (PO) cardiac hypertrophy and heart failure are associated with generalized insulin resistance and hyperinsulinemia, which may exacerbate left ventricular (LV) remodeling. While PO activates insulin receptor tyrosine kinase activity that is transduced by insulin receptor substrate 1 (IRS1), the present study tested the hypothesis that IRS1 and IRS2 have divergent effects on PO-induced LV remodeling. We therefore subjected mice with cardiomyocyte-restricted deficiency of IRS1 (CIRS1KO) or IRS2 (CIRS2KO) to PO induced by transverse aortic constriction (TAC). In WT mice, TAC-induced LV hypertrophy was associated with hyperactivation of IRS1 and Akt1, but not IRS2 and Akt2. CIRS1KO hearts were resistant to cardiac hypertrophy and heart failure in concert with attenuated Akt1 activation. In contrast, CIRS2KO hearts following TAC developed more severe LV dysfunction than WT controls, and this was prevented by haploinsufficiency of Akt1. Failing human hearts exhibited isoform-specific IRS1 and Akt1 activation, while IRS2 and Akt2 activation were unchanged. Kinomic profiling identified IRS1 as a potential regulator of cardioprotective protein kinase G-mediated signaling. In addition, gene expression profiling revealed that IRS1 signaling may promote a proinflammatory response following PO. Together, these data identify IRS1 and Akt1 as critical signaling nodes that mediate LV remodeling in both mice and humans.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1172/jci.insight.134920DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7213803PMC
March 2020

Pharmacological vs Exercise Stress Echocardiography for Detection of Cardiac Allograft Vasculopathy.

Mayo Clin Proc Innov Qual Outcomes 2020 Feb 8;4(1):65-75. Epub 2020 Jan 8.

Division of Cardiovascular Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City.

Objective: To test the hypothesis that exercise and dobutamine would provide levels of cardiac stress that are comparable to those achieved in a general stress test population, and to one another, in heart transplant recipients.

Patients And Methods: From February 10, 2015, to December 31, 2017, 81 patients underwent exercise stress (N=45) or dobutamine stress (N=36) echocardiography at a mean ± SD of 11±14 years (range, 1-29 years) after heart transplant. Hemodynamic and inotropic responses were compared between groups, and to a prior test, longitudinally. The primary outcome was peak heart rate (HR) × systolic blood pressure (SBP).

Results: Peak exercise HR × SBP × 10 was a mean ± SD of 24.9±4.9 mm Hg/min for exercise stress vs 21.2±3.4 mm Hg/min during dobutamine stress (<.001). In 35 patients who underwent a dobutamine stress test followed later by another dobutamine stress test, peak HR × SBP changed by 4.2%±16% (=.05). In 25 patients who underwent a dobutamine stress test followed later by an exercise stress test, peak HR × SBP increased by 12%±23% (=.002 vs serial dobutamine stress tests). Peak exercise HR did not correlate with time since heart transplant, patient age, or graft age. Peak dobutamine HR correlated modestly with patient age ( =0.28). Inotropic responses were similar in both groups. Overall, patients preferred exercise stress testing to dobutamine stress tests. Dobutamine stress testing was more expensive than exercise stress tests.

Conclusion: Exercise induces a level of cardiac stress that is equal to or greater than dobutamine-induced stress, at lower cost, in heart transplant recipients who express preference for exercise stress testing.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.mayocpiqo.2019.09.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7011003PMC
February 2020

Synergistic inhibition of GP130 and ERK signaling blocks chemoresistant bladder cancer cell growth.

Cell Signal 2019 11 30;63:109381. Epub 2019 Jul 30.

Department of Urology, Yale University, New Haven, CT, USA. Electronic address:

Multidrug resistance is a major treatment obstacle for recurrent and metastatic bladder cancer, which often leads to disease progression and poor clinical outcome. Although overexpression of interleukin-6 (IL-6) appears to play a critical role in the development of chemotherapy resistance, inhibitors for IL-6 alone have not improved clinical outcomes. Since the IL-6/IL-6R/GP130 complex is involved in multidrug resistance, another strategy would be to focus on glycoprotein-130 (GP130) since it dimerizes with IL-6R/CD26 as a membrane-bound signaling transducer receptor and initiates subsequent signaling activation and may be a potential therapeutic target. Currently, the role of GP130 in chemoresistant bladder cancer is unknown. In the present study, we demonstrate that GP130 is over-expressed in cisplatin and gemcitabine-resistant bladder cancer cells, and that the inhibition of GP130 expression significantly reduces cell viability, survival and migration. Downstream of GP130 is PI3K/AKT/mTOR signaling, which is inactivated by SC144, a GP130 inhibitor. However, Raf/MEK/ERK signaling, which also is downstream of GP130 is activated by SC144. This activation is likely based on a mTOR/S6K1/PI3K/ERK negative feedback loop, which is presumed to counteract the inhibitory effect of SC144 on tumor aggressiveness. Blocking both GP130 and pERK resulted in synergistic inhibition of cytotoxicity, clonal survival rates and cell migration in our chemotherapy resistant bladder cancer cells. This vertical inhibition offers a novel therapeutic strategy for targeting human chemoresistant bladder cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cellsig.2019.109381DOI Listing
November 2019

Brain TACE (Tumor Necrosis Factor-α-Converting Enzyme) Contributes to Sympathetic Excitation in Heart Failure Rats.

Hypertension 2019 07 3;74(1):63-72. Epub 2019 Jun 3.

From the Department of Internal Medicine (Y.Y., Y.C., B.B., X.C., R.M.W., R.B.F., S.-G.W.), University of Iowa Carver College of Medicine.

TNF-α (tumor necrosis factor-α) is initially synthesized as a transmembrane protein that is cleaved by TACE (TNF-α-converting enzyme) to release soluble TNF-α. The elevated level of TNF-α in the brain and circulation in heart failure (HF) suggests an increase in the TACE-mediated ectodomain shedding process. The present study sought to determine whether TACE is upregulated in cardiovascular/autonomic brain regions like subfornical organ and hypothalamic paraventricular nucleus in rats with ischemia-induced HF and whether TACE plays a role in TNF-α-driven sympathetic excitation. We found that TACE was expressed throughout the subfornical organ and paraventricular nucleus, with significantly higher levels in HF than in sham-operated (Sham) rats. Intracerebroventricular injection of recombinant TACE induced a mild increase in blood pressure, heart rate, and renal sympathetic nerve activity that peaked at 15 to 20 minutes in both Sham and HF rats. HF rats had a secondary prolonged increase in these variables that was prevented by the TNF-α inhibitor SPD304. Intracerebroventricular administration of the TACE inhibitor TNF-alpha protease inhibitor 1 decreased blood pressure, heart rate, and renal sympathetic nerve activity in Sham and HF rats, with an exaggerated reduction in heart rate and renal sympathetic nerve activity in the HF rats. Direct microinjection of TACE or TNF-alpha protease inhibitor 1 into paraventricular nucleus or subfornical organ of Sham and HF rats elicited blood pressure, heart rate, and renal sympathetic nerve activity responses similar to intracerebroventricular TACE or TNF-alpha protease inhibitor 1. Intracerebroventricular infusion of Ang II (angiotensin II) and IL (interleukin)-1β increased TACE expression in subfornical organ and paraventricular nucleus of normal rats. These data suggest that a TACE-mediated increase in soluble TNF-α in the brain contributes to sympathetic excitation in HF.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/HYPERTENSIONAHA.119.12651DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6639045PMC
July 2019

E-C coupling structural protein junctophilin-2 encodes a stress-adaptive transcription regulator.

Science 2018 12 8;362(6421). Epub 2018 Nov 8.

Department of Internal Medicine, Abboud Cardiovascular Research Center, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.

Junctophilin-2 (JP2) is a structural protein required for normal excitation-contraction (E-C) coupling. After cardiac stress, JP2 is cleaved by the calcium ion-dependent protease calpain, which disrupts the E-C coupling ultrastructural machinery and drives heart failure progression. We found that stress-induced proteolysis of JP2 liberates an N-terminal fragment (JP2NT) that translocates to the nucleus, binds to genomic DNA, and controls expression of a spectrum of genes in cardiomyocytes. Transgenic overexpression of JP2NT in mice modifies the transcriptional profile, resulting in attenuated pathological remodeling in response to cardiac stress. Conversely, loss of nuclear JP2NT function accelerates stress-induced development of hypertrophy and heart failure in mutant mice. These data reveal a self-protective mechanism in failing cardiomyocytes that transduce mechanical information (E-C uncoupling) into salutary transcriptional reprogramming in the stressed heart.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/science.aan3303DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6336677PMC
December 2018

Glycoprotein-130 Expression Is Associated with Aggressive Bladder Cancer and Is a Potential Therapeutic Target.

Mol Cancer Ther 2019 02 31;18(2):413-420. Epub 2018 Oct 31.

Department of Urology, Yale University, New Haven, Connecticut.

Predicting bladder cancer progression is important in selecting the optimal treatment for bladder cancer. Because current diagnostic factors regarding progression are lacking, new factors are needed to further stratify the curative potential of bladder cancer. Glycoprotein-130 (GP130), a transmembrane protein, is central to a number of signal transduction pathways involved in tumor aggressiveness, making it an attractive target. We hypothesize that if GP130 is found in an aggressive population of bladder tumors, then blocking GP130 expression may inhibit bladder cancer growth. Herein, we quantitatively show, using 11 patient samples and four bladder cancer cell lines, that GP130 is expressed in the aggressive human bladder tumors and in high-grade bladder cancer cell lines. Moreover, GP130 is significantly correlated with tumor grade, node category, tumor category, and patient outcome. We demonstrated a tumor-specific GP130 effect by blocking GP130 expression in bladder tumor cells, which resulted in decreased cell viability and reduced cell migration. Furthermore, we reduced tumor volume by approximately 70% compared with controls by downregulating GP130 expression using chitosan-functionalized nanoparticles encapsulating GP130 siRNA in an bladder cancer xenograft mouse model. Our results indicate that GP130 expression is linked to the aggressiveness of bladder tumors, and blocking GP130 has therapeutic potential in controlling tumor growth.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1535-7163.MCT-17-1079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6363894PMC
February 2019

Sex differences in the central and peripheral manifestations of ischemia-induced heart failure in rats.

Am J Physiol Heart Circ Physiol 2019 01 5;316(1):H70-H79. Epub 2018 Oct 5.

Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa , Iowa City, Iowa.

Sex differences in the presentation, outcome, and responses to treatment of systolic heart failure (HF) have been reported. In the present study, we examined the effect of sex on central neural mechanisms contributing to neurohumoral excitation and its peripheral manifestations in rats with HF. Male and female Sprague-Dawley rats underwent coronary artery ligation (CL) to induce HF. Age-matched rats served as controls. Ischemic zone and left ventricular function were similar 24 h and 4 wk after CL. Female rats with HF had a lower mortality rate and less hemodynamic compromise, pulmonary congestion, and right ventricular remodeling 4 wk after CL. Plasma angiotensin II (ANG II), arginine vasopressin (AVP), and norepinephrine levels were increased in HF rats in both sexes, but AVP and norepinephrine levels increased less in female rats. In the hypothalamic paraventricular nucleus, a key cardiovascular-related nucleus contributing to neurohumoral excitation in HF, mRNA levels for the proinflammatory cytokines tumor necrosis factor-α and interleukin-1β as well as cyclooxygenase-2 and the ANG II type 1a receptor were increased in HF rats of both sexes, but less so in female rats. Angiotensin-converting enzyme 2 protein levels increased in female HF rats but decreased in male HF rats. mRNA levels of AVP were lower in female rats in both control and HF groups compared with the respective male groups. Activation of extracellular signal-regulated protein kinases 1 and 2 increased similarly in both sexes in HF. The results suggest that female HF rats have less central neural excitation and less associated hemodynamic compromise than male HF rats with the same degree of initial ischemic cardiac injury. NEW & NOTEWORTHY Sex differences in the presentation and responses to treatment of heart failure (HF) are widely recognized, but the underlying mechanisms are poorly understood. The present study describes sex differences in the central nervous system mechanisms that drive neurohumoral excitation in ischemia-induced HF. Female rats had a less intense central neurochemical response to HF and experienced less hemodynamic compromise. Sex hormones may contribute to these differences in the central and peripheral adaptations to HF.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1152/ajpheart.00499.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6383354PMC
January 2019

Arginine vasopressin infusion is sufficient to model clinical features of preeclampsia in mice.

JCI Insight 2018 10 4;3(19). Epub 2018 Oct 4.

Department of Pharmacology.

Copeptin, a marker of arginine vasopressin (AVP) secretion, is elevated throughout human pregnancies complicated by preeclampsia (PE), and AVP infusion throughout gestation is sufficient to induce the major phenotypes of PE in mice. Thus, we hypothesized a role for AVP in the pathogenesis of PE. AVP infusion into pregnant C57BL/6J mice resulted in hypertension, renal glomerular endotheliosis, intrauterine growth restriction, decreased placental growth factor (PGF), altered placental morphology, placental oxidative stress, and placental gene expression consistent with human PE. Interestingly, these changes occurred despite a lack of placental hypoxia or elevations in placental fms-like tyrosine kinase-1 (FLT1). Coinfusion of AVP receptor antagonists and time-restricted infusion of AVP uncovered a mid-gestational role for the AVPR1A receptor in the observed renal pathologies, versus mid- and late-gestational roles for the AVPR2 receptor in the blood pressure and fetal phenotypes. These findings demonstrate that AVP is sufficient to initiate phenotypes of PE in the absence of placental hypoxia, and indicate that AVP may mechanistically (independently, and possibly synergistically with hypoxia) contribute to the development of clinical signs of PE in specific subtypes of human PE. Additionally, they identify divergent and gestational time-specific signaling mechanisms that mediate the development of PE phenotypes in response to AVP.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1172/jci.insight.99403DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6237463PMC
October 2018

Targeting Calpain for Heart Failure Therapy: Implications From Multiple Murine Models.

JACC Basic Transl Sci 2018 Aug 28;3(4):503-517. Epub 2018 Aug 28.

Division of Cardiovascular Medicine, Department of Internal Medicine & François M. Abboud Cardiovascular Research Center, University of Iowa Carver College of Medicine; Iowa City, Iowa.

Heart failure remains a major cause of morbidity and mortality in developed countries. There is still a strong need to devise new mechanism-based treatments for heart failure. Numerous studies have suggested the importance of the Ca-dependent protease calpain in cardiac physiology and pathology. However, no drugs are currently under development or testing in human patients to target calpain for heart failure treatment. Herein the data demonstrate that inhibition of calpain activity protects against deleterious ultrastructural remodeling and cardiac dysfunction in multiple rodent models of heart failure, providing compelling evidence that calpain inhibition is a promising therapeutic strategy for heart failure treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jacbts.2018.05.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6115647PMC
August 2018

Discovery of an Experimental Model of Unicuspid Aortic Valve.

J Am Heart Assoc 2018 06 30;7(13). Epub 2018 Jun 30.

Division of Cardiovascular Medicine, Carver College of Medicine University of Iowa, Iowa City, IA.

Background: The epithelial growth factor receptor family of tyrosine kinases modulates embryonic formation of semilunar valves. We hypothesized that mice heterozygous for a dominant loss-of-function mutation in epithelial growth factor receptor, which are mice, would develop anomalous aortic valves, valve dysfunction, and valvular cardiomyopathy.

Methods And Results: Aortic valves from mice and control mice were examined by light microscopy at 2.5 to 4 months of age. Additional and control mice underwent echocardiography at 2.5, 4.5, 8, and 12 months of age, followed by histologic examination. In young mice, microscopy revealed anatomic anomalies in 79% of aortic valves, which resembled human unicuspid aortic valves. Anomalies were not observed in control mice. At 12 months of age, histologic architecture was grossly distorted in aortic valves. Echocardiography detected moderate or severe aortic regurgitation, or aortic stenosis was present in 38% of mice at 2.5 months of age (N=24) and in 74% by 8 months of age. Left ventricular enlargement, hypertrophy, and reversion to a fetal myocardial gene expression program occurred in mice with aortic valve dysfunction, but not in mice with near-normal aortic valve function. Myocardial fibrosis was minimal or absent in all groups.

Conclusions: A new mouse model uniquely recapitulates salient functional, structural, and histologic features of human unicuspid aortic valve disease, which are phenotypically distinct from other forms of congenital aortic valve disease. The new model may be useful for elucidating mechanisms by which congenitally anomalous aortic valves become critically dysfunctional.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/JAHA.117.006908DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6064885PMC
June 2018

Legends in Urology.

Authors:
Robert M Weiss

Can J Urol 2018 06;25(3):9296-9299

Donald Guthrie Professor of Urology, Director, Pediatric Urology, Yale University School of Medicine, New Haven, CT, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
June 2018

Angiotensin II Type 1a Receptors in the Subfornical Organ Modulate Neuroinflammation in the Hypothalamic Paraventricular Nucleus in Heart Failure Rats.

Neuroscience 2018 06 21;381:46-58. Epub 2018 Apr 21.

Department of Internal Medicine, University of Iowa Carver College of Medicine, 200 Hawkins Drive, Iowa City, IA, USA; Research Service, Veterans Affairs Medical Center, 601 Highway 6 West, Iowa City, IA, USA. Electronic address:

Inflammation in the hypothalamic paraventricular nucleus (PVN) contributes to neurohumoral excitation and its adverse consequences in systolic heart failure (HF). The stimuli that trigger inflammation in the PVN in HF are not well understood. Angiotensin II (AngII) has pro-inflammatory effects, and circulating levels of AngII increase in HF. The subfornical organ (SFO), a circumventricular structure that lacks an effective blood-brain barrier and senses circulating AngII, contains PVN-projecting neurons. We hypothesized that activation of AngII type 1a receptors (ATR) in the SFO induces neuroinflammation downstream in the PVN. Male rats received SFO microinjections of an adeno-associated virus carrying shRNA for ATR, a scrambled shRNA, or vehicle. One week later, some rats were euthanized to confirm the transfection potential and knockdown efficiency of the shRNA. Others underwent coronary artery ligation to induce HF or a sham coronary artery ligation (Sham). Four weeks later, HF rats that received the scrambled shRNA had increased mRNA in SFO and PVN for ATR, inflammatory mediators and indicators of neuronal and glial activation, increased plasma levels of AngII, tumor necrosis factor-α, norepinephrine and arginine vasopressin, and impaired cardiac function, compared with Sham rats that received scrambled shRNA. The central abnormalities were ameliorated in HF rats that received ATR shRNA, as were plasma norepinephrine and vasopressin. Sham rats that received ATR shRNA had reduced SFO ATR mRNA but no other changes compared with Sham rats that received scrambled shRNA. The results suggest that activation of ATR in the SFO upregulates the neuroinflammation in the PVN that contributes to neurohumoral excitation in HF.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.neuroscience.2018.04.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5960439PMC
June 2018

Lipopolysaccharide-induced maternal inflammation induces direct placental injury without alteration in placental blood flow and induces a secondary fetal intestinal injury that persists into adulthood.

Am J Reprod Immunol 2018 05 25;79(5):e12816. Epub 2018 Jan 25.

University of Iowa, Iowa City, IA, USA.

Problem: Premature birth complicates 10%-12% of deliveries. Infection and inflammation are the most common etiologies and are associated with increased offspring morbidity and mortality. We hypothesize that lipopolysaccharide (LPS)-induced maternal inflammation causes direct placenta injury and subsequent injury to the fetal intestine.

Method Of Study: Pregnant C57Bl6 mice were injected intraperitoneally on day 15.5 with 100 μg/kg LPS or saline. Maternal serum, amniotic fluid, placental samples, and ileal samples of offspring were obtained assessed for inflammation and/or injury. Maternal placental ultrasounds were performed. Placental DNA was isolated for microbiome analysis.

Results: Maternal injection with LPS caused elevated IL-1β, IL-10, IL-6, KC-GRO, and TNF. Placental tissue showed increased IL-1β, IL-6, and KC-GRO and decreased IL-10, but no changes were observed in amniotic fluid. Placental histology demonstrated LPS-induced increases in mineralization and necrosis, but no difference in placental blood flow. Most placentas had no detectable microbiome. Exposure to maternal LPS induced significant injury to the ilea of the offspring.

Conclusion: Lipopolysaccharide causes a maternal inflammatory response that is mirrored in the placenta. Placental histology demonstrates structural changes; however, placental blood flow is preserved. LPS also induces an indirect intestinal injury in the offspring that lasts beyond the neonatal period.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/aji.12816DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5908742PMC
May 2018

Role of myeloperoxidase in abdominal aortic aneurysm formation: mitigation by taurine.

Am J Physiol Heart Circ Physiol 2017 Dec 29;313(6):H1168-H1179. Epub 2017 Sep 29.

Division of Cardiology, Department of Medicine, Medical College of Georgia at Augusta University, Augusta, Georgia;

Oxidative stress plays a fundamental role in abdominal aortic aneurysm (AAA) formation. Activated polymorphonuclear leukocytes (or neutrophils) are associated with AAA and express myeloperoxidase (MPO), which promotes inflammation, matrix degradation, and other pathological features of AAA, including enhanced oxidative stress through generation of reactive oxygen species. Both plasma and aortic MPO levels are elevated in patients with AAA, but the role of MPO in AAA pathogenesis has, heretofore, never been investigated. Here, we show that MPO gene deletion attenuates AAA formation in two animal models: ANG II infusion in apolipoprotein E-deficient mice and elastase perfusion in C57BL/6 mice. Oral administration of taurine [1% or 4% (wt/vol) in drinking water], an amino acid known to react rapidly with MPO-generated oxidants like hypochlorous acid, also prevented AAA formation in the ANG II and elastase models as well as the CaCl application model of AAA formation while reducing aortic peroxidase activity and aortic protein-bound dityrosine levels, an oxidative cross link formed by MPO. Both MPO gene deletion and taurine supplementation blunted aortic macrophage accumulation, elastin fragmentation, and matrix metalloproteinase activation, key features of AAA pathogenesis. Moreover, MPO gene deletion and taurine administration significantly attenuated the induction of serum amyloid A, which promotes ANG II-induced AAAs. These data implicate MPO in AAA pathogenesis and suggest that studies exploring whether taurine can serve as a potential therapeutic for the prevention or treatment of AAA in patients merit consideration. Neutrophils are abundant in abdominal aortic aneurysm (AAA), and myeloperoxidase (MPO), prominently expressed in neutrophils, is associated with AAA in humans. This study demonstrates that MPO gene deletion or supplementation with the natural product taurine, which can scavenge MPO-generated oxidants, can prevent AAA formation, suggesting an attractive potential therapeutic strategy for AAA.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1152/ajpheart.00296.2017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5814655PMC
December 2017

MG53 is dispensable for T-tubule maturation but critical for maintaining T-tubule integrity following cardiac stress.

J Mol Cell Cardiol 2017 11 16;112:123-130. Epub 2017 Aug 16.

Division of Cardiovascular Medicine, Department of Internal Medicine, Abboud Cardiovascular Research Center, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA; Department of Veterans Affairs Medical Center, Iowa City, IA 52242, USA. Electronic address:

The cardiac transverse (T)-tubule membrane system is the safeguard for cardiac function and undergoes dramatic remodeling in response to cardiac stress. However, the mechanism by which cardiomyocytes repair damaged T-tubule network remains unclear. In the present study, we tested the hypothesis that MG53, a muscle-specific membrane repair protein, antagonizes T-tubule damage to protect against maladaptive remodeling and thereby loss of excitation-contraction coupling and cardiac function. Using MG53-knockout (MG53-KO) mice, we first established that deficiency of MG53 had no impact on maturation of the T-tubule network in developing hearts. Additionally, MG53 ablation did not influence T-tubule integrity in unstressed adult hearts as late as 10months of age. Following left ventricular pressure overload-induced cardiac stress, MG53 protein levels were increased by approximately three-fold in wild-type mice, indicating that pathological stress induces a significant upregulation of MG53. MG53-deficient mice had worsened T-tubule disruption and pronounced dysregulation of Ca handling properties, including decreased Ca transient amplitude and prolonged time to peak and decay. Moreover, MG53 deficiency exacerbated cardiac hypertrophy and dysfunction and decreased survival following cardiac stress. Our data suggest MG53 is not required for T-tubule development and maintenance in normal physiology. However, MG53 is essential to preserve T-tubule integrity and thereby Ca handling properties and cardiac function under pathological cardiac stress.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.yjmcc.2017.08.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5682927PMC
November 2017