Heart failure (HF) is characterized by global alterations in myocardial DNA methylation, yet little is known about epigenetic regulation of the non-coding genome and potential reversibility of DNA methylation with left ventricular assist device (LVAD) therapy. Genome-wide mapping of myocardial DNA methylation in 36 HF patients at LVAD implantation, 8 patients at LVAD explantation, and 7 non-failing donors using a high-density bead array platform identified 2079 differentially methylated positions (DMPs) in ischemic cardiomyopathy and 261 DMPs in non-ischemic cardiomyopathy. LVAD support resulted in normalization of only 3.2% of HF-associated DMPs. Methylation-expression correlation analysis yielded several protein-coding genes that are hypomethylated and upregulated (HTRA1, FBXO16, EFCAB13, AKAP13) or hypermethylated and downregulated (TBX3) in HF. A novel cardiac-specific super-enhancer lncRNA (LINC00881) is hypermethylated and downregulated in human HF. LINC00881 is an upstream regulator of sarcomere and calcium channel gene expression including MYH6, CACNA1C, and RYR2. LINC00881 knockdown reduces peak calcium amplitude in the beating human iPS cell derived cardiomyocytes. Collectively, these data suggest that HF-associated changes in myocardial DNA methylation within coding and non-coding genome are minimally reversible with mechanical unloading. Epigenetic reprogramming strategies may be necessary to achieve sustained clinical recovery from heart failure.
Xianghai Liao, Peter J. Kennel, Bohao Liu, Trevor R. Nash, Richard Z. Zhuang, Amandine F. Godier-Furnemont, Chenyi Xue, Rong Lu, Paolo C. Colombo, Nir Uriel, Muredach P. Reilly, Steven O. Marx, Gordana Vunjak-Novakovic, Veli K. Topkara
In pulmonary arterial hypertension (PAH), inflammation promotes a fibroproliferative pulmonary vasculopathy. Reductionist studies emphasizing single biochemical reactions suggest a shift toward glycolytic metabolism in PAH; however, key questions remain regarding the metabolic profile of specific cell types within PAH vascular lesions in vivo. We used RNA-seq to profile the transcriptome of pulmonary artery endothelial cells (PAECs) freshly isolated from an inflammatory vascular injury model of PAH ex vivo, and these data were integrated with information from human gene ontology pathways. Network medicine was then used to map all amino acid and glucose pathways to the consolidated human interactome, which includes data on 233,957 physical protein-protein interactions. Glucose and proline pathways were significantly close to the human PAH disease module, suggesting that these pathways are functionally relevant to PAH pathobiology. To test this observation in vivo, we used multi-isotope imaging mass spectrometry (MIMS) to map and quantify utilization of glucose and proline in the PAH pulmonary vasculature at subcellular resolution. Our findings suggest suggest that elevated glucose and proline avidity underlies increased biomass in PAECs and the media of fibrosed PAH pulmonary arterioles. Overall, these data show that anabolic utilization of glucose and proline are fundamental to the vascular pathology of PAH.
Bradley M. Wertheim, Rui-Sheng Wang, Christelle Guillermier, Christiane V.R. Hütter, William M. Oldham, Jörg Menche, Matthew L. Steinhauser, Bradley A. Maron
Although murine models of coronary atherosclerotic disease have been used extensively to determine mechanisms, limited new therapeutic options have emerged. Pigs with familial hypercholesterolemia (FH pigs) develop complex coronary atheromas that are almost identical to human lesions. We reported previously that insulin-like growth factor 1 (IGF-1) reduced aortic atherosclerosis and promoted features of stable plaque in a murine model. We administered human recombinant IGF-1 or saline (control) in atherosclerotic FH pigs for 6 months. IGF-1 decreased relative coronary atheroma in vivo (intravascular ultrasound) and reduced lesion cross-sectional area (postmortem histology). IGF-1 increased plaque’s fibrous cap thickness, and reduced necrotic core, macrophage content, and cell apoptosis consistent with promotion of a stable plaque phenotype. IGF-1 reduced circulating triglycerides, markers of systemic oxidative stress and CXCL12 chemokine levels. We used spatial transcriptomics (ST) to identify global transcriptome changes in advanced plaque compartments and to obtain mechanistic insights into IGF-1 effects. ST analysis shows that IGF-1 suppressed FOS/FOSB factors and gene expression of MMP9 and CXCL14 in plaque macrophages, suggesting possible involvement of these molecules in IGF-1’s effect on atherosclerosis. Thus, IGF-1 reduced coronary plaque burden and promoted features of stable plaque in a pig model, providing support for consideration of clinical trials.
Sergiy Sukhanov, Yusuke Higashi, Tadashi Yoshida, Svitlana Danchuk, Mitzi Alfortish, Traci Goodchild, Amy Scarborough, Thomas E. Sharp III, James S. Jenkins, Daniel Garcia, Jan Ivey, Darla L. Tharp, Jeffrey D. Schumacher, Zach Rozenbaum, Jay K Kolls, Douglas K. Bowles, David Lefer, Patrice Delafontaine
Sinoatrial node (SAN) cells are the heart’s primary pacemaker. Their activity is tightly regulated by β-adrenergic receptor (β-AR) signaling. Adenylyl cyclase (AC) is a key enzyme in the β-AR pathway that catalyzes the production of cAMP. There are current gaps in our knowledge regarding the dominant AC isoforms and the specific roles of Ca2+-activated ACs in the SAN. The current study tests the hypothesis that distinct AC isoforms are preferentially expressed in the SAN and compartmentalize within microdomains to orchestrate heart rate regulation during β-AR signaling. In contrast to atrial and ventricular myocytes, SAN cells express a diverse repertoire of ACs, with ACI as the predominant Ca2+-activated isoform. Although ACI-KO (ACI–/–) mice exhibit normal cardiac systolic or diastolic function, they experience SAN dysfunction. Similarly, SAN-specific CRISPR/Cas9-mediated gene silencing of ACI results in sinus node dysfunction. Mechanistically, hyperpolarization-activated cyclic nucleotide-gated 4 (HCN4) channels form functional microdomains almost exclusively with ACI, while ryanodine receptor and L-type Ca2+ channels likely compartmentalize with ACI and other AC isoforms. In contrast, there were no significant differences in T-type Ca2+ and Na+ currents at baseline or after β-AR stimulation between WT and ACI–/– SAN cells. Due to its central characteristic feature as a Ca2+-activated isoform, ACI plays a unique role in sustaining the rise of local cAMP and heart rates during β-AR stimulation. The findings provide insights into the critical roles of the Ca2+-activated isoform of AC in sustaining SAN automaticity that is distinct from contractile cardiomyocytes.
Lu Ren, Phung N. Thai, Raghavender Reddy Gopireddy, Valeriy Timofeyev, Hannah A. Ledford, Ryan L. Woltz, Seojin Park, Jose L. Puglisi, Claudia M. Moreno, Luis Fernando Santana, Alana C. Conti, Michael I. Kotlikoff, Yang Kevin Xiang, Vladimir Yarov-Yarovoy, Manuela Zaccolo, Xiao-Dong Zhang, Ebenezer N. Yamoah, Manuel F. Navedo, Nipavan Chiamvimonvat
There is limited data on the link between cardiac autonomic neuropathy (CAN) and severe hypoglycemia, in type 2 diabetes. We evaluated the associations of CAN with severe hypoglycemia among 7,421 adults with type 2 diabetes from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study. CAN was defined using electrocardiogram-derived measures. Cox and Andersen-Gill regression models were used to generate hazard ratios (HRs) for first and recurrent severe hypoglycemic episodes, respectively. Over 4.7 years, there were 558 first and 811 recurrent hypoglycemic events. Participants with CAN had increased risks of first (HR 1.23, 95%CI 1.01-1.50) or recurrent (HR: 1.46, 95%CI 1.16-1.84) episodes of severe hypoglycemia. The intensity of glycemic management modified the CAN association with hypoglycemia (P for interaction <0.05). In the standard glycemic management group, compared to participants without CAN, HRs for first severe hypoglycemia and recurrent hypoglycemia were 1.58 (95%CI 1.13-2.23) and 1.96 (1.33-2.90). In the intensive glycemic management group, HRs for first severe hypoglycemia and recurrent hypoglycemia were 1.10 (0.86-1.40) and 1.24 (0.93-1.65). In summary, CAN was independently associated with higher risks of first and recurrent hypoglycemia among adults with type 2 diabetes, with the highest risk observed among those on standard glycemic management.
Arnaud D. Kaze, Matthew F. Yuyun, Rexford S. Ahima, Michael R. Rickels, Justin B. Echouffo-Tcheugui
Rest has long been considered beneficial to patient healing, yet remarkably there are no evidence-based experimental models determining how it benefits disease outcomes. Here, we create a novel experimental rest model in mice that briefly extends the morning rest period. We found, in two different major cardiovascular disease conditions (cardiac hypertrophy, myocardial infarction), that imposing a short, extended period of morning rest each day limits cardiac remodeling, as compared to controls. Mechanistically, rest mitigates autonomic-mediated hemodynamic stress on the cardiovascular system, relaxes myofilament contractility, attenuates cardiac remodeling genes, consistent with the benefits on cardiac structure and function. These same rest-responsive gene pathways underlie the pathophysiology of many major human cardiovascular conditions, as demonstrated by interrogating open-source transcriptomic data, and thus patients with other conditions may also benefit from a morning rest period in a similar manner. Our findings implicate rest as a key driver of physiology, creating an entirely new field – as broad and important as diet, sleep, or exercise – and provide a strong rationale for investigation of rest-based therapy for major clinical diseases.
Cristine J. Reitz, Mina Rasouli, Faisal J. Alibhai, Tarak Nath Khatua, W. Glen Pyle, Tami A. Martino
Gene mutations causing loss of dystrophin result in the severe muscle disease known as Duchenne muscular dystrophy (DMD). Despite efforts at genetic repair, DMD therapy remains largely palliative. Loss of dystrophin destabilizes the sarcolemmal membrane impacting mechanosensitive cation channels to increase calcium entry, promoting cell damage, and eventually muscle dysfunction. One putative channel is transient receptor potential canonical 6 (TRPC6) that we showed contributes to abnormal force and calcium stress-responses in mouse cardiomyocytes lacking dystrophin and haplodeficient in utrophin mdx/utrn+/- (HET). Here, we show in both HET and the far more severe homozygous mdx/utrn-/- (DKO) mouse that TRPC6 gene deletion or its selective pharmacologic inhibition (BI 749327) prolongs survival 2-3-fold, improving skeletal and cardiac muscle and bone defects. Gene pathways reduced by BI 749327 treatment most prominently regulate fat metabolism and TGFβ1 signaling. These results support the testing of TRPC6 inhibitors in human trials for other diseases as a novel DMD therapy.
Brian L. Lin, Joseph Y. Shin, William P.D. Jeffreys, Nadan Wang, Clarisse A. Lukban, Megan C. Moorer, Esteban Velarde, Olivia A. Hanselman, Seoyoung Kwon, Suraj Kannan, Ryan C. Riddle, Christopher W. Ward, Steven S. Pullen, Antonio Filareto, David A. Kass
Obesity is an important risk factor for atrial fibrillation (AF), but a better mechanistic understanding of obesity-related atrial fibrillation is required. Serum glucocorticoid kinase 1 (SGK1) is a kinase positioned within multiple obesity-related pathways, and prior work has shown a pathologic role of SGK1 signaling in ventricular arrhythmias. We validated a mouse model of obesity-related AF using wild type mice fed a high fat diet. RNA sequencing of atrial tissue demonstrated substantial differences in gene expression, with enrichment of multiple SGK1-related pathways, and we confirmed upregulated of SGK1 transcription, activation, and signaling in obese atria. Mice expressing a cardiac specific dominant negative SGK1 were protected from obesity-related AF, through effects on atrial electrophysiology, action potential characteristics, structural remodeling, inflammation, and sodium current. Overall, this study demonstrates the promise of targeting SGK1 in a mouse model of obesity-related AF.
Aneesh Bapat, Guoping Li, Ling Xiao, Ashish Yeri, Maarten Hulsmans, Jana Grune, Masahiro Yamazoe, Maximillian J. Schloss, Yoshiko Iwamoto, Justin G. Tedeschi, Xinyu Yang, Matthias Nahrendorf, Anthony Rosenzweig, Patrick T. Ellinor, Saumya Das, David Milan
Chitinase 3-like 1 (CHI3L1) is the prototypic chitinase-like protein mediating inflammation, cell proliferation, and tissue remodeling. Limited data suggests CHI3L1 is elevated in human pulmonary arterial hypertension (PAH) and is associated with disease severity. Despite its importance as a regulator of injury/repair responses, the relationship between CHI3L1 and pulmonary vascular remodeling is not well understood. We hypothesize that CHI3L1 and its signaling pathways contribute to the vascular remodeling responses that occur in pulmonary hypertension (PH). We examined the relationship of plasma CHI3L1 levels and severity of PH in patients with various forms of PH, including Group 1 PAH and Group 3 PH, and found that circulating levels of serum CHI3L1 were associated with worse hemodynamics and correlated directly with mean pulmonary artery pressure and pulmonary vascular resistance. We also used transgenic mice with constitutive knockout and inducible overexpression of CHI3L1 to examine its role in hypoxia-, monocrotaline-, and bleomycin-induced models of pulmonary vascular disease. In all 3 mouse models of pulmonary vascular disease, pulmonary hypertensive responses were mitigated in CHI3L1 null mice and accentuated in transgenic mice that overexpress CHI3L1. Finally, CHI3L1 alone was sufficient to induce pulmonary arterial smooth muscle cell proliferation, inhibit pulmonary vascular endothelial cell apoptosis, induce the loss of endothelial barrier function, and induce endothelial-to-mesenchymal transition. These findings demonstrate that CHI3L1 and its receptors play an integral role in pulmonary vascular disease pathobiology and may offer a novel target for the treatment PAH and PH associated with fibrotic lung disease.
Xiuna Sun, Erika Nakajima, Carmelissa Norbrun, Parand Sorkhdini, Alina Xiaoyu Yang, Dongqin Yang, Corey E. Ventetuolo, Julie Braza, Alexander Vang, Jason Aliotta, Debasree Banerjee, Mandy Pereira, Grayson Baird, Qing Lu, Elizabeth O. Harrington, Sharon Rounds, Chun Geun Lee, Hongwei Yao, Gaurav Choudhary, James R. Klinger, Yang Zhou
Membrane instability and disruption underlie myriad acute and chronic disorders. Anxa6 encodes the membrane-associated protein annexin A6 and was identified as a genetic modifier of muscle repair and muscular dystrophy. To evaluate annexin A6’s role in membrane repair in vivo, we inserted sequences encoding green fluorescent protein (GFP) into the last coding exon of Anxa6. Heterozygous Anxa6gfp mice expressed a normal pattern of annexin A6 with reduced annexin A6GFP mRNA and protein. High-resolution imaging of wounded muscle fibers showed annexin A6GFP rapidly formed a repair cap at the site of injury. Injured cardiomyocytes and neurons also displayed repair caps after wounding, highlighting annexin A6–mediated repair caps as a feature in multiple cell types. Using surface plasmon resonance, we showed recombinant annexin A6 bound phosphatidylserine-containing lipids in a Ca2+- and dose-dependent fashion with appreciable binding at approximately 50 μM Ca2+. Exogenously added recombinant annexin A6 localized to repair caps and improved muscle membrane repair capacity in a dose-dependent fashion without disrupting endogenous annexin A6 localization, indicating annexin A6 promotes repair from both intracellular and extracellular compartments. Thus, annexin A6 orchestrates repair in multiple cell types, and recombinant annexin A6 may be useful in additional chronic disorders beyond skeletal muscle myopathies.
Alexis R. Demonbreun, Elena Bogdanovic, Lauren A. Vaught, Nina L. Reiser, Katherine S. Fallon, Ashlee M. Long, Claire C. Oosterbaan, Michele Hadhazy, Patrick G.T. Page, Prem Raj B. Joseph, Gabrielle Cowen, Alexander M. Telenson, Ammaarah Khatri, Katherine R. Sadleir, Robert Vassar, Elizabeth M. McNally
No posts were found with this tag.