All Publications


  • Adverse effects of air pollution-derived fine particulate matter on cardiovascular homeostasis and disease. Trends in cardiovascular medicine Bae, H. R., Chandy, M., Aguilera, J., Smith, E. M., Nadeau, K. C., Wu, J. C., Paik, D. T. 2021

    Abstract

    Air pollution is a rapidly growing major health concern around the world. Atmospheric particulate matter that has a diameter of less than 2.5 m (PM2.5) refers to an air pollutant composed of particles and chemical compounds that originate from various sources. While epidemiological studies have established the association between PM2.5 exposure and cardiovascular diseases, the precise cellular and molecular mechanisms by which PM2.5 promotes cardiovascular complications are yet to be fully elucidated. In this review, we summarize the various sources of PM2.5, its components, and the concentrations of ambient PM2.5 in various settings. We discuss the experimental findings to date that evaluate the potential adverse effects of PM2.5 on cardiovascular homeostasis and function, and the possible therapeutic options that may alleviate PM2.5-driven cardiovascular damage.

    View details for DOI 10.1016/j.tcm.2021.09.010

    View details for PubMedID 34619335

  • Endocardial/endothelial angiocrines regulate cardiomyocyte development and maturation and induce features of ventricular non-compaction. European heart journal Rhee, S., Paik, D. T., Yang, J. Y., Nagelberg, D., Williams, I., Tian, L., Roth, R., Chandy, M., Ban, J., Belbachir, N., Kim, S., Zhang, H., Phansalkar, R., Wong, K. M., King, D. A., Valdez, C., Winn, V. D., Morrison, A. J., Wu, J. C., Red-Horse, K. 2021

    Abstract

    AIMS: Non-compaction cardiomyopathy is a devastating genetic disease caused by insufficient consolidation of ventricular wall muscle that can result in inadequate cardiac performance. Despite being the third most common cardiomyopathy, the mechanisms underlying the disease, including the cell types involved, are poorly understood. We have previously shown that endothelial cell-specific deletion of the chromatin remodeller gene Ino80 results in defective coronary vessel development that leads to ventricular non-compaction in embryonic mouse hearts. We aimed to identify candidate angiocrines expressed by endocardial and ECs inwildtype and LVNC conditions in Tie2Cre;Ino80fl/fl transgenic embryonic mouse hearts, and test the effect of these candidates on cardiomyocyte proliferation and maturation.METHODS AND RESULTS: We used single-cell RNA-sequencing to characterize endothelial and endocardial defects in Ino80-deficient hearts. We observed a pathological endocardial cell population in the non-compacted hearts and identified multiple dysregulated angiocrine factors that dramatically affected cardiomyocyte behaviour. We identified Col15A1 as a coronary vessel-secreted angiocrine factor, downregulated by Ino80-deficiency, that functioned to promote cardiomyocyte proliferation. Furthermore, mutant endocardial and endothelial cells (ECs) up-regulated expression of secreted factors, such as Tgfbi, Igfbp3, Isg15, and Adm, which decreased cardiomyocyte proliferation and increased maturation.CONCLUSIONS: These findings support a model where coronary ECs normally promote myocardial compaction through secreted factors, but that endocardial and ECs can secrete factors that contribute to non-compaction under pathological conditions.

    View details for DOI 10.1093/eurheartj/ehab298

    View details for PubMedID 34279605

  • Method for selective ablation of undifferentiated human pluripotent stem cell populations for cell-based therapies. JCI insight Chour, T., Tian, L., Lau, E., Thomas, D., Itzhaki, I., Malak, O., Zhang, J. Z., Qin, X., Wardak, M., Liu, Y., Chandy, M., Black, K. E., Lam, M. P., Neofytou, E., Wu, J. C. 2021; 6 (7)

    Abstract

    Human pluripotent stem cells (PSCs), which are composed of embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), provide an opportunity to advance cardiac cell therapy-based clinical trials. However, an important hurdle that must be overcome is the risk of teratoma formation after cell transplantation due to the proliferative capacity of residual undifferentiated PSCs in differentiation batches. To tackle this problem, we propose the use of a minimal noncardiotoxic doxorubicin dose as a purifying agent to selectively target rapidly proliferating stem cells for cell death, which will provide a purer population of terminally differentiated cardiomyocytes before cell transplantation. In this study, we determined an appropriate in vitro doxorubicin dose that (a) eliminates residual undifferentiated stem cells before cell injection to prevent teratoma formation after cell transplantation and (b) does not cause cardiotoxicity in ESC-derived cardiomyocytes (CMs) as demonstrated through contractility analysis, electrophysiology, topoisomerase activity assay, and quantification of reactive oxygen species generation. This study establishes a potentially novel method for tumorigenic-free cell therapy studies aimed at clinical applications of cardiac cell transplantation.

    View details for DOI 10.1172/jci.insight.142000

    View details for PubMedID 33830086

  • Atlas of Exosomal microRNAs Secreted From Human iPSC-Derived Cardiac Cell Types. Circulation Chandy, M., Rhee, J., Ozen, M. O., Williams, D. R., Pepic, L., Liu, C., Zhang, H., Malisa, J., Lau, E., Demirci, U., Wu, J. C. 2020; 142 (18): 1794–96

    View details for DOI 10.1161/CIRCULATIONAHA.120.048364

    View details for PubMedID 33136510

  • Patient and Disease-Specific Induced Pluripotent Stem Cells for Discovery of Personalized Cardiovascular Drugs and Therapeutics. Pharmacological reviews Paik, D. T., Chandy, M. n., Wu, J. C. 2020; 72 (1): 320–42

    Abstract

    Human induced pluripotent stem cells (iPSCs) have emerged as an effective platform for regenerative therapy, disease modeling, and drug discovery. iPSCs allow for the production of limitless supply of patient-specific somatic cells that enable advancement in cardiovascular precision medicine. Over the past decade, researchers have developed protocols to differentiate iPSCs to multiple cardiovascular lineages, as well as to enhance the maturity and functionality of these cells. Despite significant advances, drug therapy and discovery for cardiovascular disease have lagged behind other fields such as oncology. We speculate that this paucity of drug discovery is due to a previous lack of efficient, reproducible, and translational model systems. Notably, existing drug discovery and testing platforms rely on animal studies and clinical trials, but investigations in animal models have inherent limitations due to interspecies differences. Moreover, clinical trials are inherently flawed by assuming that all individuals with a disease will respond identically to a therapy, ignoring the genetic and epigenomic variations that define our individuality. With ever-improving differentiation and phenotyping methods, patient-specific iPSC-derived cardiovascular cells allow unprecedented opportunities to discover new drug targets and screen compounds for cardiovascular disease. Imbued with the genetic information of an individual, iPSCs will vastly improve our ability to test drugs efficiently, as well as tailor and titrate drug therapy for each patient.

    View details for DOI 10.1124/pr.116.013003

    View details for PubMedID 31871214

  • A tangled tale of microRNA and cardiac fibrosis. Clinical science (London, England : 1979) Chandy, M. 2019; 133 (21): 2217–20

    Abstract

    Cardiac fibrosis is important for wound healing, regeneration and producing the extracellular matrix (ECM) that provides the scaffold for cells. In pathological situations, fibroblasts are activated and remodel the ECM. In volume 133, issue 17 of Clinical Science, Yang et al. discovered that the miR-214-3p/NLRC5 axis is important for fibroblast-to-myofibroblast transition (FMT) and ECM remodelling in a pressure overload model of fibrosis [Clin. Sci. (2019) 133(17), 1845-1856]. This discovery helps to explain the complicated regulation of cardiac fibrosis. It also underscores the need for more investigation into the mechanisms of cardiac fibrosis to develop better diagnostic modalities and therapeutic options in heart failure.

    View details for DOI 10.1042/CS20190866

    View details for PubMedID 31722012

  • c-Myb regulates transcriptional activation of miR-143/145 in vascular smooth muscle cells PLOS ONE Chandy, M., Ishida, M., Shikatani, E. A., El-Mounayri, O., Park, L., Afroze, T., Wang, T., Marsden, P. A., Husain, M. 2018; 13 (8): e0202778

    Abstract

    MicroRNAs (miR) are small non-coding RNAs that regulate diverse biological functions. The bicistronic gene miR-143/145 determines cell fate and phenotype of vascular smooth muscle cells (VSMC), in part, by destabilizing Elk-1 mRNA. The transcription factor c-Myb also regulates differentiation and proliferation of VSMC, and here we test whether these effects may be mediated by miR-143/145.Flow cytometry of cardiovascular-directed d3.75 embryoid bodies (EBs) isolated smooth muscle progenitors with specific cell surface markers. In c-myb knockout (c-myb -/-) EB, these progenitors manifest low levels of miR-143 (19%; p<0.05) and miR-145 (6%; p<0.01) expression as compared to wild-type (wt) EB. Primary VSMC isolated from transgenic mice with diminished expression (c-myblx/lx) or reduced activity (c-mybh/h) of c-Myb also manifest low levels of miR-143 (c-myblx/lx: 50%; c-mybh/h: 41%), and miR-145 (c-myblx/lx: 49%; c-mybh/h: 56%), as compared to wt (P<0.05). Sequence alignment identified four putative c-Myb binding sites (MBS1-4) in the proximal promoter (PP) of the miR-143/145 gene. PP-reporter constructs revealed that point mutations in MBS1 and MBS4 abrogated c-Myb-dependent transcription from the miR-143/145 PP (P<0.01). Chromatin immunoprecipitation (ChIP) revealed preferential c-Myb binding at MBS4 (p<0.001). By conjugating Elk-1 3'-untranslated region (UTR) to a reporter and co-transducing wt VSMC with this plus a miR-143-antagomir, and co-transducing c-myblx/lx VSMC with this plus a miR-143-mimic, we demonstrate that c-Myb's ability to repress Elk-1 is mediated by miR-143.c-Myb regulates VSMC gene expression by transcriptional activation of miR-143/145.

    View details for DOI 10.1371/journal.pone.0202778

    View details for Web of Science ID 000443374400013

    View details for PubMedID 30169548

    View details for PubMedCentralID PMC6118359

  • CARDIOPROTECTIVE BENEFITS OF COMBINED TREATMENT WITH GLUCAGON-LIKE PEPTIDE-1 RECEPTOR AGONIST & SODIUM GLUCOSE TRANSPORTER-2 INHIBITOR IN MICE Khat, D., Momen, A., Siraj, M. A., Hadipour-Lakmehsari, S., Chandy, M. J., Husain, M. ELSEVIER IRELAND LTD. 2018: 111
  • Skin-derived precursors from human subjects with Type 2 diabetes yield dysfunctional vascular smooth muscle cells CLINICAL SCIENCE Steinbach, S. K., Yau, T. M., Ouzounian, M., Abdel-Qadir, H., Chandy, M., Waddell, T. K., Husain, M. 2017; 131 (15): 1801–14

    Abstract

    Objective: Few methods enable molecular and cellular studies of vascular aging or Type 2 diabetes (T2D). Here, we report a new approach to studying human vascular smooth muscle cell (VSMC) pathophysiology by examining VSMCs differentiated from progenitors found in skin. Approach and results: Skin-derived precursors (SKPs) were cultured from biopsies (N=164, ∼1 cm2) taken from the edges of surgical incisions of older adults (N=158; males 72%; mean age 62.7 ± 13 years) undergoing cardiothoracic surgery, and differentiated into VSMCs at high efficiency (>80% yield). The number of SKPs isolated from subjects with T2D was ∼50% lower than those without T2D (cells/g: 0.18 ± 0.03, N=58 versus 0.40 ± 0.05, N=100, P<0.05). Importantly, SKP-derived VSMCs from subjects with T2D had higher Fluo-5F-determined baseline cytosolic Ca2+ concentrations (AU: 1,968 ± 160, N=7 versus 1,386 ± 170, N=13, P<0.05), and a trend toward greater Ca2+ cycling responses to norepinephrine (NE) (AUC: 177,207 ± 24,669, N=7 versus 101,537 ± 15,881, N=20, P<0.08) despite a reduced frequency of Ca2+ cycling (events s-1 cell-1: 0.011 ± 0.004, N=8 versus 0.021 ± 0.003, N=19, P<0.05) than those without T2D. SKP-derived VSMCs from subjects with T2D also manifest enhanced sensitivity to phenylephrine (PE) in an impedance-based assay (EC50 nM: 72.3 ± 63.6, N=5 versus 3,684 ± 3,122, N=9, P<0.05), and impaired wound closure in vitro (% closure: 21.9 ± 3.6, N=4 versus 67.0 ± 10.3, N=4, P<0.05). Compared with aortic- and saphenous vein-derived primary VSMCs, SKP-derived VSMCs are functionally distinct, but mirror defects of T2D also exhibited by primary VSMCs.Skin biopsies from older adults yield sufficient SKPs to differentiate VSMCs, which reveal abnormal phenotypes of T2D that survive differentiation and persist even after long-term normoglycemic culture.

    View details for DOI 10.1042/CS20170239

    View details for Web of Science ID 000406139100003

    View details for PubMedID 28424290

  • c-Myb Regulates Proliferation and Differentiation of Adventitial Sca1(+) Vascular Smooth Muscle Cell Progenitors by Transactivation of Myocardin ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY Shikatani, E. A., Chandy, M., Besla, R., Li, C. C., Momen, A., El-Mounayri, O., Robbins, C. S., Husain, M. 2016; 36 (7): 1367-+

    Abstract

    Vascular smooth muscle cells (VSMCs) are believed to dedifferentiate and proliferate in response to vessel injury. Recently, adventitial progenitor cells were implicated as a source of VSMCs involved in vessel remodeling. c-Myb is a transcription factor known to regulate VSMC proliferation in vivo and differentiation of VSMCs from mouse embryonic stem cell-derived progenitors in vitro. However, the role of c-Myb in regulating specific adult vascular progenitor cell populations was not known. Our objective was to examine the role of c-Myb in the proliferation and differentiation of Sca1(+) adventitial VSMC progenitor cells.Using mice with wild-type or hypomorphic c-myb (c-myb(h/h)), BrdU (bromodeoxyuridine) uptake and flow cytometry revealed defective proliferation of Sca1(+) adventitial VSMC progenitor cells at 8, 14, and 28 days post carotid artery denudation injury in c-myb(h/h) arteries. c-myb(h/h) cKit(+)CD34(-)Flk1(-)Sca1(+)CD45(-)Lin(-) cells failed to proliferate, suggesting that c-myb regulates the activation of specific Sca1(+) progenitor cells in vivo and in vitro. Although expression levels of transforming growth factor-β1 did not vary between wild-type and c-myb(h/h) carotid arteries, in vitro differentiation of c-myb(h/h) Sca1(+) cells manifested defective transforming growth factor-β1-induced VSMC differentiation. This is mediated by reduced transcriptional activation of myocardin because chromatin immunoprecipitation revealed c-Myb binding to the myocardin promoter only during differentiation of Sca1(+) cells, myocardin promoter mutagenesis identified 2 specific c-Myb-responsive binding sites, and adenovirus-mediated expression of myocardin rescued the phenotype of c-myb(h/h) progenitors.These data support a role for c-Myb in the regulation of VSMC progenitor cells and provide novel insight into how c-myb regulates VSMC differentiation through myocardin.

    View details for DOI 10.1161/ATVBAHA.115.307116

    View details for Web of Science ID 000378497000011

    View details for PubMedID 27174098

  • Delayed Tamponade after Traumatic Wound with Left Ventricular Compression CASE REPORTS IN CARDIOLOGY Almehmadi, F., Chandy, M., Connelly, K. A., Edwards, J. 2016: 2154748

    Abstract

    Delayed cardiac tamponade after a penetrating chest injury is a rare complication. The clinical diagnosis of tamponade is facilitated with imaging. We present a case report of a 23-year-old male who was brought to emergency after multiple stab wounds to the chest. After resuscitation and repair of laceration of right internal mammary artery and right ventricle, he was discharged but later returned with shortness of breath. Echocardiography revealed a rare case of delayed pericardial tamponade causing left ventricular collapse. The pericardial effusion was treated with emergent pericardiocentesis and later required a thoracoscopy guided pericardial window for definitive management.

    View details for DOI 10.1155/2016/2154748

    View details for Web of Science ID 000383082900001

    View details for PubMedID 27651957

    View details for PubMedCentralID PMC5019924

  • Successful rapid intravenous desensitization for radioiodine contrast allergy in a patient requiring urgent coronary angiography JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY-IN PRACTICE Gandhi, S., Litt, D., Chandy, M., Nguyen, B. M., Jindal, N., Tarlo, S. M., Overgaard, C. B. 2014; 2 (1): 101–2

    View details for DOI 10.1016/j.jaip.2013.06.016

    View details for Web of Science ID 000354197300017

    View details for PubMedID 24565778

  • RPAP1, a novel human RNA polymerase II-associated protein affinity purified with recombinant wild-type and mutated polymerase subunits MOLECULAR AND CELLULAR BIOLOGY Jeronimo, C., Langelier, M. F., Zeghouf, M., Cojocaru, M., Bergeron, D., Baali, D., Forget, D., Mnaimneh, S., Davierwala, A. P., Pootoolal, J., Chandy, M., Canadien, Beattie, B. K., Richards, D. P., Workman, J. L., Hughes, T. R., Greenblatt, J., Coulombe, B. 2004; 24 (16): 7043–58

    Abstract

    We have programmed human cells to express physiological levels of recombinant RNA polymerase II (RNAPII) subunits carrying tandem affinity purification (TAP) tags. Double-affinity chromatography allowed for the simple and efficient isolation of a complex containing all 12 RNAPII subunits, the general transcription factors TFIIB and TFIIF, the RNAPII phosphatase Fcp1, and a novel 153-kDa polypeptide of unknown function that we named RNAPII-associated protein 1 (RPAP1). The TAP-tagged RNAPII complex is functionally active both in vitro and in vivo. A role for RPAP1 in RNAPII transcription was established by shutting off the synthesis of Ydr527wp, a Saccharomyces cerevisiae protein homologous to RPAP1, and demonstrating that changes in global gene expression were similar to those caused by the loss of the yeast RNAPII subunit Rpb11. We also used TAP-tagged Rpb2 with mutations in fork loop 1 and switch 3, two structural elements located strategically within the active center, to start addressing the roles of these elements in the interaction of the enzyme with the template DNA during the transcription reaction.

    View details for DOI 10.1128/MCB.24.16.7043-7058.2004

    View details for Web of Science ID 000223045600015

    View details for PubMedID 15282305

    View details for PubMedCentralID PMC479746

  • Function and selectivity of bromodomains in anchoring chromatin-modifying complexes to promoter nucleosomes CELL Hassan, A. H., Prochasson, P., Neely, K. E., Galasinski, S. C., Chandy, M., Carrozza, M. J., Workman, J. L. 2002; 111 (3): 369-379

    Abstract

    The functions of the SAGA and SWI/SNF complexes are interrelated and can form stable "epigenetic marks" on promoters in vivo. Here we show that stable promoter occupancy by SWI/SNF and SAGA in the absence of transcription activators requires the bromodomains of the Swi2/Snf2 and Gcn5 subunits, respectively, and nucleosome acetylation. This acetylation can be brought about by either the SAGA or NuA4 HAT complexes. The bromodomain in the Spt7 subunit of SAGA is dispensable for this activity but will anchor SAGA if it is swapped into Gcn5, indicating that specificity of bromodomain function is determined in part by the subunit it occupies. Thus, bromodomains within the catalytic subunits of SAGA and SWI/SNF anchor these complexes to acetylated promoter nucleosomes.

    View details for Web of Science ID 000179010100009

    View details for PubMedID 12419247

  • A zebrafish Ftz-F1 (Fushi Tarazu Factor 1) homologue requires multiple subdomains in the D and E regions for its transcriptional activity JOURNAL OF BIOLOGICAL CHEMISTRY Liu, D., Chandy, M., Lee, S. K., Le Drean, Y., Ando, H., Xiong, F., Lee, J. W., Hew, C. L. 2000; 275 (22): 16758–66

    Abstract

    A zebrafish Ftz-F1 homologue, zFF1A (zebrafish Ff1a or Nr5a2, a member of nuclear receptor superfamily) and its C-terminally truncated variant (zFF1B) were previously identified. Due to lack of the identity box (I-box) and activation function 2 (AF-2) domain, zFF1B lacks transactivation function and fails to synergize with estrogen receptor (ER) in regulating promoters. It was speculated that the I-box might be involved in the zFF1A/ER interaction. In the present study, the function of the I-box was examined. In the absence of the I-box or with an altered heptad 9, the AF-2 of zFF1A was not functional, either in the presence or absence of ER. The GST pull-down assay showed that zFF1A and its mutants exerted similar physical contacts with ER-LBD, suggesting that the "dimerization" domain (I-box) is essential for the transcriptional activity of zFF1A. Moreover, nuclear receptor coactivator selectively activated zFF1 with the I-box but exerted no effect on zFF1B, indicating that the I-box is able to interact with the coactivators. By deletion study and analysis of the identified domains in GAL4-DNA binding domain, other regions of zFF1A critical for its AF were also delineated. Consistent with the mutation analysis, AF-2 was active only in the presence of the I-box. We also identified a novel AF domain (AF-3) located in the hinge region (amino acids 155-267), although the activity of AF-3 was inhibited by its flanking region. We suggest that the D and E regions of zFF1A possess both positive and negative transactivation functions, and interdomain "cross-talk" may confer the full transcriptional activity of the protein.

    View details for DOI 10.1074/jbc.M000121200

    View details for Web of Science ID 000087392200052

    View details for PubMedID 10747875