Browsing by Author "Pacak, Karel"

Now showing 1 - 3 of 3
  • Thumbnail Image
    Item
    A remarkable adaptive paradigm of heart performance and protection emerges in response to marked cardiac-specific overexpression of ADCY8
    (eLife Sciences, 2022-12-14) Tarasov, Kirill V.; Chakir, Khalid; Riordon, Daniel R.; Lyashkov, Alexey E.; Ahmet, Ismayil; Perino, Maria Grazia; Silvester, Allwin Jennifa; Zhang, Jing; Wang, Mingyi; Lukyanenko, Yevgeniya O.; Qu, Jia-Hua; Barrera, Miguel Calvo-Rubio; Juhaszova, Magdalena; Tarasova, Yelena S.; Ziman, Bruce; Telljohann, Richard; Kumar, Vikas; Ranek, Mark; Lammons, John; Bychkov, Rostislav; de Cabo, Rafael; Jun, Seungho; Keceli, Gizem; Gupta, Ashish; Yang, Dongmei; Aon, Miguel A.; Adamo, Luigi; Morrell, Christopher H.; Otu, Walter; Carroll, Cameron; Chambers, Shane; Paolocci, Nazareno; Huynh, Thanh; Pacak, Karel; Weiss, Robert; Field, Loren; Sollott, Steven J.; Lakatta, Edward G.; Medicine, School of Medicine
    Adult (3 month) mice with cardiac-specific overexpression of adenylyl cyclase (AC) type VIII (TGAC8) adapt to an increased cAMP-induced cardiac workload (~30% increases in heart rate, ejection fraction and cardiac output) for up to a year without signs of heart failure or excessive mortality. Here, we show classical cardiac hypertrophy markers were absent in TGAC8, and that total left ventricular (LV) mass was not increased: a reduced LV cavity volume in TGAC8 was encased by thicker LV walls harboring an increased number of small cardiac myocytes, and a network of small interstitial proliferative non-cardiac myocytes compared to wild type (WT) littermates; Protein synthesis, proteosome activity, and autophagy were enhanced in TGAC8 vs WT, and Nrf-2, Hsp90α, and ACC2 protein levels were increased. Despite increased energy demands in vivo LV ATP and phosphocreatine levels in TGAC8 did not differ from WT. Unbiased omics analyses identified more than 2,000 transcripts and proteins, comprising a broad array of biological processes across multiple cellular compartments, which differed by genotype; compared to WT, in TGAC8 there was a shift from fatty acid oxidation to aerobic glycolysis in the context of increased utilization of the pentose phosphate shunt and nucleotide synthesis. Thus, marked overexpression of AC8 engages complex, coordinate adaptation "circuity" that has evolved in mammalian cells to defend against stress that threatens health or life (elements of which have already been shown to be central to cardiac ischemic pre-conditioning and exercise endurance cardiac conditioning) that may be of biological significance to allow for proper healing in disease states such as infarction or failure of the heart.
  • Thumbnail Image
    Item
    Developmental vascular malformations in EPAS1 gain-of-function syndrome
    (American Society for Clinical Investigation, 2021-03-08) Rosenblum, Jared S.; Wang, Herui; Dmitriev, Pauline M.; Cappadona, Anthony J.; Mastorakos, Panagiotis; Xu, Chen; Jha, Abhishek; Edwards, Nancy; Donahue, Danielle R.; Munasinghe, Jeeva; Nazari, Matthew A.; Knutsen, Russell H.; Rosenblum, Bruce R.; Smirniotopoulos, James G.; Pappo, Alberto; Spetzler, Robert F.; Vortmeyer, Alexander; Gilbert, Mark R.; McGavern, Dorian B.; Chew, Emily; Kozel, Beth A.; Heiss, John D.; Zhuang, Zhengping; Pacak, Karel; Pathology and Laboratory Medicine, School of Medicine
    Mutations in EPAS1, encoding hypoxia-inducible factor-2α (HIF-2α), were previously identified in a syndrome of multiple paragangliomas, somatostatinoma, and polycythemia. HIF-2α, when dimerized with HIF-1β, acts as an angiogenic transcription factor. Patients referred to the NIH for new, recurrent, and/or metastatic paraganglioma or pheochromocytoma were confirmed for EPAS1 gain-of-function mutation; imaging was evaluated for vascular malformations. We evaluated the Epas1A529V transgenic syndrome mouse model, corresponding to the mutation initially detected in the patients (EPAS1A530V), for vascular malformations via intravital 2-photon microscopy of meningeal vessels, terminal vascular perfusion with Microfil silicate polymer and subsequent intact ex vivo 14T MRI and micro-CT, and histologic sectioning and staining of the brain and identified pathologies. Further, we evaluated retinas from corresponding developmental time points (P7, P14, and P21) and the adult dura via immunofluorescent labeling of vessels and confocal imaging. We identified a spectrum of vascular malformations in all 9 syndromic patients and in all our tested mutant mice. Patient vessels had higher variant allele frequency than adjacent normal tissue. Veins of the murine retina and intracranial dura failed to regress normally at the expected developmental time points. These findings add vascular malformation as a new clinical feature of EPAS1 gain-of-function syndrome.
  • Thumbnail Image
    Item
    Head and neck paraganglioma in Pacak-Zhuang syndrome
    (Oxford University Press, 2025) Rosenblum, Jared S.; Cole, Yasemin; Dang, Danielle; Lookian, Pashayar P.; Alkaissi, Hussam; Patel, Mayank; Cappadona, Anthony J.; Jha, Abhishek; Edwards, Nancy; Donahue, Danielle R.; Munasinghe, Jeeva; Wang, Herui; Knutsen, Russell H.; Pappo, Alberto S.; Lechan, Ronald M.; Kozel, Beth A.; Smirniotopoulos, James G.; Kim, H. Jeffrey; Vortmeyer, Alexander; Miettinen, Markku; Heiss, John D.; Zhuang, Zhengping; Pacak, Karel; Pathology and Laboratory Medicine, School of Medicine
    Background: Head and neck paragangliomas (HNPGLs) are typically slow-growing, hormonally inactive tumors of parasympathetic paraganglia. Inactivation of prolyl-hydroxylase domain-containing 2 protein causing indirect gain-of-function of hypoxia-inducible factor-2α (HIF-2α), encoded by EPAS1, was recently shown to cause carotid body hyperplasia. We previously described a syndrome with multiple sympathetic paragangliomas caused by direct gain-of-function variants in EPAS1 (Pacak-Zhuang syndrome, PZS) and developed a corresponding mouse model. Methods: We evaluated a cohort of patients with PZS (n = 9) for HNPGL by positron emission tomography, magnetic resonance imaging, and computed tomography and measured carotid body size compared to literature reference values. Resected tumors were evaluated by histologic sectioning and staining. We evaluated the corresponding mouse model at multiple developmental stages (P8 and adult) for lesions of the head and neck by high resolution ex vivo imaging and performed immunohistochemical staining on histologic sections of the identified lesions. Results: hree patients had imaging consistent with HNPGL, one of which warranted resection and was confirmed on histology. Three additional patients had carotid body enlargement (Z-score > 2.0), and 3 had carotid artery malformations. We found that 9 of 10 adult variant mice had carotid body tumors and 6 of 8 had a paraganglioma on the cranio-caval vein, the murine homologue of the superior vena cava; these were also found in 4 of 5 variant mice at post-natal day 8. These tumors and the one resected from a patient were positive for tyrosine hydroxylase, synaptophysin, and chromogranin A. Brown fat in a resected patient tumor carried the EPAS1 pathogenic variant. Conclusions: These findings (1) suggest HNPGL as a feature of PZS and (2) show that these pathogenic variants are sufficient to cause the development of these tumors, which we believe represents a continuous spectrum of disease starting from hyperplasia.