Sivareddy Kotla, PhD
Department of Cardiology, Division of Internal Medicine
About Dr. Kotla
Dr. Kotla has spent the last decade on the regulation of signal transduction mechanisms in the cardiovascular system. After completing his undergraduate/Master of Sciences in Biotechnology and Ph.D. in Biotechnology (2008-2013) from the Jawaharlal Nehru Technological University- Indian Veterinary Research Institute, India. Much of his doctoral work focused on foot-and-mouth disease virus (FMDV) biology, including vaccine efficacy and immune responses. He undertook his post-doctoral training at the University of Tennessee Health Science Center, Department of Physiology, Tennessee, Memphis (2012 – 2015), studying redox regulation of vascular inflammation and atherosclerosis with Dr. G.N Rao. He was then promoted to junior faculty (Research Instructor) at the University of Tennessee Health Science Center in 2015. In August of 2017, he joined the faculty at The University of Texas MD Anderson Cancer Center at Houston in the Department of Cardiology. With these training experiences and collaborating with Dr. Jun-ichi Abe he has expanded his research through use of transgenic and knock out mouse models to study molecular mechanisms of cardio toxicity associated with cancer treatments. The Kotla’s research uses an integrated approach from molecules, cell-based, metabolism, animal models, mitochondria biology towards these goals.
Present Title & Affiliation
Primary Appointment
Assistant Professor, Department of Cardiology - Research, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX
Research Interests
Besides the significant improvement in patient survival rate, modern cancer therapies including chemotherapy, radiotherapy, targeted therapy and immunotherapy, main cause of the cardio-toxicity and cardiovascular complications. The molecular pathways that contribute to cancer therapy-associated cardio toxicity and cardiovascular complications are not well understood. The Kotla’s main research aim to understand the molecular pathways that contribute to cardio toxicity associated with the cancer treatments. We highlight recent discoveries from our studies below.
Role of telomere dysfunction in regulating senescence-associated secretory phenotype and consequent Endothelial cell activation and atherosclerosis.
Recently, we are working on the role of premature ageing in cancer treatments-mediated cardiovascular disease. During the course of our study, we discover the unique and interesting role of telomeric repeat-binding factor 2-interacting protein (TERF2IP), a member of the shelterin complex at the telomere, in EC activation and atherogenesis. Furthermore, we investigated TERF2IP-dependent gene expression and its role in regulating mechano-signaling -induced senescence-associated secretory phenotype (SASP). We found that MKRN1 and RICTOR belong to a distinct reciprocal gene set that is both negatively and positively regulated by p90RSK. TERF2IP S205 phosphorylation, a downstream event of p90RSK activation, uniquely inhibits MKRN1 expression and contributes to EC activation and senescence, which are key events for atherogenesis.Determine the molecular mechanisms of "trained immunity" induced by Cardiovascular toxic drugs including HIV and cancer treatments.
Recently, Dr. Kotla’s reported that various drugs including the combination antiretroviral therapy (cART) used in HIV therapies, ionizing radiation (IR) and ponatinib used in cancer therapies also can induce p90RSK activation, which "prime" the cells to the secondary toxicity insults, leading to the senescent phenotypes sustained chronic inflammation. As such, our report underscores the importance of p90RSK regulation in monocytes/macrophages as a viable biomarker and therapeutic target for preventing cardiovascular disease, especially in HIV + patients treated with cART.Study the link between nucleus and mitochondria in regulating chemo- and radiation therapy-induced cardiovascular disease:
We found p90RSK-ERK5 S496 phosphorylation as the shared signaling event induced by various cancer treatments. Furthermore, we showed that it plays a key role in establishing the crosstalk and feedback loop between the mt and the nucleus through mitochondrial hibernation- induced PARP activation. The initiation of this crosstalk process leads to priming of monocytes and macrophages in response to secondary ROS insults and future CVD in cancer survivors. On the basis of the results of our pre-clinical study, we found that PARP inhibitor is one of the candidates that inhibits IR-induced mt hibernation and may lead to the use of PARP inhibitors, not only as radio-sensitizers but also in the prevention of CVD after RT.Establish the cancer therapy-induced atherosclerosis mouse model and the role of ERK5 post translational modifications in EC activation after radiation exposure:
We established a reliable and reproducible cancer treatments-induced vascular dysfunction and atherosclerosis model, which can represent cardiovascular disease in cancer survivors. We demonstrate that ionizing radiation (IR) not only increases atherosclerotic events but also vulnerable plaque formation. We established the proper animal model to study how to minimize the cardiovascular toxicity due to cancer treatment. We also showed the critical role of p90RSK-medaited ERK5 SUMOylation in regulating endothelial cell activation after IR exposure.Education & Training
Degree-Granting Education
| 2013 | Indian Veterinary Research Institute - Jawaharlal Nehru Technological University, Bangalore, Hyderabad, IND, PHD, Biotechnology |
| 2005 | Bangalore University, Bangalore, Karnataka, IND, MS, Biotechnology |
| 2003 | Sri Krishnadevaraya University, Anantapur, Andhra Pradesh, IND, BS, Microbiology |
Postgraduate Training
| 2015-2017 | Research instructor, Instructor, Department of Physiology, University of Tennessee Health Science Center, Memphis, TN |
| 2012-2015 | Postdoctoral Research Trainee, Postdoctoral Research Trainee, Department of Physiology, University of Tennessee Health Science Center, Memphis |
| 2011-2012 | Senior Research Assistant, Department of Physiology, University of Tennessee Health Science Center, Memphis, TN |
Experience & Service
Academic Appointments
Research Instructor, Department of Physiology, University of Tennessee Health Science Center, Memphis, TN, 2015 - 2017
Postdoctoral Research Trainee, Department of Physiology, University of Tennessee Health Science Center, Memphis, SD, 2012 - 2015
Senior Research Assistant, Department of Physiology, University of Tennessee Health Science Center, Memphis, TN, 2011 - 2012
Senior Research Fellow, Department of Molecular Virology, India Veterinary Research Institute, Bangalore, 2007 - 2011
Project Assistant, Department of Virology, Project Directorate of Animal disease monitoring and surveillance, Bangalore, 2005 - 2007
Honors & Awards
| 2015 | Outstanding Postdoctoral Research Achievement Award, University of Tennessee Health Science Center |
| 2014 | Outstanding Postdoctoral Research Achievement Award, University of Tennessee Health Science Center |
| 2011 | Outstanding Young Biotechnologist Award, SAB India |
| 2010 | Best Paper Presentation Award, Indian Virology Society |
Selected Publications
Peer-Reviewed Articles
- Wang Y, Abe JI, Chau KM, Wang Y, Vu HT, Reddy Velatooru L, Gulraiz F, Imanishi M, Samanthapudi VSK, Nguyen MTH, Ko KA, Lee LL, Thomas TN, Olmsted-Davis EA, Kotla S, Fujiwara K, Cooke JP, Zhao D, Evans SE, Le NT. MAGI1 inhibits interferon signaling to promote influenza A infection. Front Cardiovasc Med 9:791143, 2022. e-Pub 2022. PMID: 36082118.
- Imanishi M, Cheng H, Kotla S, Deswal A, Le NT, Chini E, Ko KA, Samanthapudi VSK, Lee LL, Herrmann J, Xu X, Reyes-Gibby C, Yeung SJ, Schadler KL, Yusuf SW, Liao Z, Nurieva R, Amir ED, Burks JK, Palaskas NL, Cooke JP, Lin SH, Kobayashi M, Yoshimoto M, Abe JI. Radiation therapy induces immunosenescence mediated by p90RSK. Front Cardiovasc Med 9:988713, 2022. e-Pub 2022. PMID: 36426217.
- Velatooru LR, Abe RJ, Imanishi M, Gi YJ, Ko KA, Heo KS, Fujiwara K, Le NT, Kotla S. Disturbed flow-induced FAK K152 SUMOylation initiates the formation of pro-inflammation positive feedback loop by inducing reactive oxygen species production in endothelial cells. Free Radic Biol Med 177:404-418, 2021. e-Pub 2021. PMID: 34619327.
- Kotla S, Zhang A, Imanishi M, Ko KA, Lin SH, Gi YJ, Moczygemba M, Isgandarova S, Schadler KL, Chung C, Milgrom SA, Banchs J, Yusuf SW, Amaya DN, Guo H, Thomas TN, Shen YH, Deswal A, Herrmann J, Kleinerman ES, Entman ML, Cooke JP, Schifitto G, Maggirwar SB, McBeath E, Gupte AA, Krishnan S, Patel ZS, Yoon Y, Burks JK, Fujiwara K, Brookes PS, Le NT, Hamilton DJ, Abe JI. Nucleus-mitochondria positive feedback loop formed by ERK5 S496 phosphorylation-mediated poly (ADP-ribose) polymerase activation provokes persistent pro-inflammatory senescent phenotype and accelerates coronary atherosclerosis after chemo-radiation. Redox Biol 47:102132, 2021. e-Pub 2021. PMID: 34619528.
- Mahalingam R, Dharmalingam P, Santhanam A, Kotla S, Davuluri G, Karmouty-Quintana H, Ashrith G, Thandavarayan RA. Single-cell RNA sequencing analysis of SARS-CoV-2 entry receptors in human organoids. J Cell Physiol 236(4):2950-2958, 2021. e-Pub 2020. PMID: 32944935.
- Abe RJ, Savage H, Imanishi M, Banerjee P, Kotla S, Paez-Mayorga J, Taunton J, Fujiwara K, Won JH, Yusuf SW, Palaskas NL, Banchs J, Lin SH, Schadler KL, Abe JI, Le NT. Corrigendum: p90RSK-MAGI1 Module Controls Endothelial Permeability by Post-translational Modifications of MAGI1 and Hippo Pathway. Front Cardiovasc Med 8:663486, 2021. e-Pub 2021. PMID: 33681312.
- Banerjee P, Kotla S, Reddy Velatooru L, Abe RJ, Davis EA, Cooke JP, Schadler K, Deswal A, Herrmann J, Lin SH, Abe JI, Le NT. Senescence-Associated Secretory Phenotype as a Hinge Between Cardiovascular Diseases and Cancer. Front Cardiovasc Med 8:763930, 2021. e-Pub 2021. PMID: 34746270.
- Abe RJ, Savage H, Imanishi M, Banerjee P, Kotla S, Paez-Mayorga J, Taunton J, Fujiwara K, Won JH, Yusuf SW, Palaskas NL, Banchs J, Lin SH, Schadler KL, Abe JI, Le NT. p90RSK-MAGI1 Module Controls Endothelial Permeability by Post-translational Modifications of MAGI1 and Hippo Pathway. Front Cardiovasc Med 7, 2020. PMID: 33304925.
- Kotla S, Le NT, Vu HT, Ko KA, Gi YJ, Thomas TN, Giancursio C, Lusis AJ, Cooke JP, Fujiwara K, Abe JI. Endothelial senescence-associated secretory phenotype (SASP) is regulated by Makorin-1 ubiquitin E3 ligase. Metabolism 100:153962, 2019. e-Pub 2019. PMID: 31476350.
- Kotla S, Vu HT, Ko KA, Wang Y, Imanishi M, Heo KS, Fujii Y, Thomas TN, Gi YJ, Mazhar H, Paez-Mayorga J, Shin JH, Tao Y, Giancursio CJ, Medina JL, Taunton J, Lusis AJ, Cooke JP, Fujiwara K, Le NT, Abe JI. Endothelial senescence is induced by phosphorylation and nuclear export of telomeric repeat binding factor 2-interacting protein. JCI Insight 4(9), 2019. e-Pub 2019. PMID: 31045573.
- Abe JI, Ko KA, Kotla S, Wang Y, Paez-Mayorga J, Shin IJ, Imanishi M, Vu HT, Tao Y, Leiva-Juarez MM, Thomas TN, Medina JL, Won JH, Fujii Y, Giancursio CJ, McBeath E, Shin JH, Guzman L, Abe RJ, Taunton J, Mochizuki N, Faubion W, Cooke JP, Fujiwara K, Evans SE, Le NT. MAGI1 as a link between endothelial activation and ER stress drives atherosclerosis. JCI Insight 4(7), 2019. e-Pub 2019. PMID: 30944250.
- Singh MV, Kotla S, Le NT, Ae Ko K, Heo KS, Wang Y, Fujii Y, Thi Vu H, McBeath E, Thomas TN, Jin Gi Y, Tao Y, Medina JL, Taunton J, Carson N, Dogra V, Doyley MM, Tyrell A, Lu W, Qiu X, Stirpe NE, Gates KJ, Hurley C, Fujiwara K, Maggirwar SB, Schifitto G, Abe JI. Senescent Phenotype Induced by p90RSK-NRF2 Signaling Sensitizes Monocytes and Macrophages to Oxidative Stress in HIV-Positive Individuals. Circulation 139(9):1199-1216, 2019. PMID: 30586719.
- Vu HT, Kotla S, Ko KA, Fujii Y, Tao Y, Medina J, Thomas T, Hada M, Sood AK, Singh PK, Milgrom SA, Krishnan S, Fujiwara K, Le NT, Abe JI. Ionizing Radiation Induces Endothelial Inflammation and Apoptosis via p90RSK-Mediated ERK5 S496 Phosphorylation. Front Cardiovasc Med 5:23, 2018. e-Pub 2018. PMID: 29594152.
- Ko KA, Wang Y, Kotla S, Fujii Y, Vu HT, Venkatesulu BP, Thomas TN, Medina JL, Gi YJ, Hada M, Grande-Allen J, Patel ZS, Milgrom SA, Krishnan S, Fujiwara K, Abe JI. Developing a Reliable Mouse Model for Cancer Therapy-Induced Cardiovascular Toxicity in Cancer Patients and Survivors. Front Cardiovasc Med 5:26, 2018. e-Pub 2018. PMID: 29675417.
- Paez-Mayorga J, Chen AL, Kotla S, Tao Y, Abe RJ, He ED, Danysh BP, Hofmann MC, Le NT. Ponatinib Activates an Inflammatory Response in Endothelial Cells via ERK5 SUMOylation. Front Cardiovasc Med 5:125, 2018. e-Pub 2018. PMID: 30238007.
- Kotla S, Singh NK, Kirchhofer D, Rao GN. Heterodimers of the transcriptional factors NFATc3 and FosB mediate tissue factor expression for 15(S)-hydroxyeicosatetraenoic acid-induced monocyte trafficking. J Biol Chem 292(36):14885-14901, 2017. e-Pub 2017. PMID: 28724635.
- Kotla S, Singh NK, Rao GN.. ROS via BTK-p300-STAT1-PPARγ signaling activation mediates cholesterol crystals-induced CD36 expression and foam cell formation. Redox Biology 11:350-364, 2017. PMID: 28040503.
- Kotla S, Sanghratna Vishanath B, H J D, K G, V V S S, Reddy GR. DNA vaccine (P1-2A- 3C pCDNA) co-administered with Bovine IL-18 gives protective immune response against Foot and Mouth Disease in cattle. Vet Microbiol 193:106-15, 2016. e-Pub 2016. PMID: 27599937.
- Janjanam J, Chandaka GK, Kotla S, Rao GN. PLCβ3 mediates cortactin interaction with WAVE2 in MCP1-induced actin polymerization and cell migration. Mol Biol Cell 26(25):4589-606, 2015. e-Pub 2015. PMID: 26490115.
- Singh NK, Kotla S, Kumar R, Rao GN. Cyclic AMP Response Element Binding Protein Mediates Pathological Retinal Neovascularization via Modulating DLL4-NOTCH1 Signaling. EBioMedicine 2(11):1767-1784, 2015. e-Pub 2015. PMID: 26870802.
- Singh NK, Kotla S, Dyukova E, Traylor JG, Orr AW, Chernoff J, Marion TN, Rao GN. Disruption of p21-activated kinase 1 gene diminishes atherosclerosis in apolipoprotein E- deficient mice. Nat Commun 6:7450, 2015. e-Pub 2015. PMID: 26104863.
- Kotla S, Singh NK, Traylor JG Jr, Orr AW, Rao GN.. ROS-dependent Syk and Pyk2- mediated STAT1 activation is required for 15(S)-hydroxyeicosatetraenoic acid-induced CD36 expression and foam cell formation. Free Radic Biol Med 76:147-62, 2014. PMID: 2515225.
- Kotla S, Singh NK, Heckle MR, Tigyi GJ, Rao GN. The transcription factor CREB enhances interleukin-17A production and inflammation in a mouse model of atherosclerosis. Sci Signal 6(293):ra83, 2013. e-Pub 2013. PMID: 24045154.
- Singh NK, Kundumani-Sridharan V, Kumar S, Verma SK, Kotla S, Mukai H, Heckle MR, Rao GN. Protein kinase N1 is a novel substrate of NFATc1-mediated cyclin D1- CDK6 activity and modulates vascular smooth muscle cell division and migration leading to inward blood vessel wall remodeling. J Biol Chem 287(43):36291-304, 2012. e-Pub 2012. PMID: 22893700.
- Kotla S, Rashmi BR, Dechamma HJ, Gopalakrishna S, Banumathi N, Suryanarayana VV, Reddy GR.. Cationic micro particle [poly (D,L-lactide-co-glycolide)]-coated DNA vaccination induces a long-term immune response against foot and mouth disease in guinea pigs. J Gene Med 14(5):348-52, 2012. PMID: 22438260.
- Jadav SK, Kotla S, Rashmi BR, Dechamma HJ, Ganesh K, Suryanarayana VV, Reddy GR.. Improved immune response by ID-pVAC: a secretory DNA vaccine construct delivered by PLG micro particles against foot and mouth disease in guinea pigs. Res Vet Sci 91(1):86-9, 2011. PMID: 20884037.
- Kotla S, Rao DM, Dechamma HJ, Suryanarayana VV, Reddy GR.. Expression of bovine (Bos indicus) interleukin-18 in Escherichia coli and its biological activity. Microbiol Immunol 54(9):564-7, 2010. PMID: 20840156.
- Kotla S, Muralidhar Rao D, Badrinaryana N, Suryanaryana VV, Reddy GR.. Enhancement of DNA vaccine (P12A3C-pcDNA) efficacy against foot-and-mouth disease by co administration of interleukin-18-expressing (IL18 pcDNA) plasmid in guinea pigs. FEMS Immunol Med Microbiol 60(3):261-268, 2010. PMID: 21039923.
Grant & Contract Support
| Title: | Pathological flow-induced endothelial damage and plaque erosion |
| Funding Source: | NIH/NHLBI |
| Role: | Co-Investigator |
| Title: | Mitigating radiation-induced cardiovascular disease by inhibiting pre-mature aging |
| Funding Source: | NIH/NIAID |
| Role: | Co-Investigator |
| Title: | Metabolite profiling in radiation-induced cardiovascular disease |
| Funding Source: | UT MD Anderson Cancer Center |
| Role: | Principal Investigator |
| Title: | Risk Factors and Mechanisms of Radiation -Induced Cardiovascular Disease |
| Funding Source: | Multidisciplinary Research Program, MD Anderson Cancer Center |
| Role: | Co-Principal Investigator |
| Title: | Inducible epithelial resistance: a program investigating mechanisms to protect against acute and chronic complications of pneumonia |
| Funding Source: | NIH/NHLBI |
| Role: | Co-Investigator |