On October 7, 2022, the LSU Health Sciences Foundation held the formal investiture of Hung Wen "Kevin" Lin, PhD, as the Joanna Gunning Magale Endowed Professor of Neurology. An endowed professorship is among the highest honors that can be bestowed on a faculty member.
Hung Wen (Kevin) Lin, PhD
Associate Professor of Neurology
BS, University of Wisconsin-Madison (Biochemistry, 1995-1999)
PhD, Southern Illinois University, School of Medicine (Pharmacology, 2001-2007)
Post-Doctoral Fellow, University of Miami, Miller School of Medicine, (Neurology, 2007-2012)
On May 25, 2021, Alexandre de Couto e Silva received his PhD after successfully defending his dissertation on "Neuro-resilient function of PRMT8 against cellular stress."
Four trainees in the Center for Cardiovascular Diseases and Sciences at LSU Health Shreveport recently received American Heart Association Fellowships to fund their Pre-doctoral and Post-doctoral Training.
The research focus in the Lin Lab is on cerebral vascular innervations and involves the characterization of novel signaling agents. The importance of identifying novel factors that influence cerebral blood flow autoregulation and innovative neuroprotective agents in the context of cardiopulmonary resuscitation and stroke are my long-term research goals. Dr. Lin previously discovered, a new vasotone regulatory agent (Lin HW et al., PNAS, 2008), namely the release of palmitic acid methyl ester (a vasodilator and neuroprotective agent that is more potent than some nitric oxide donors) and stearic acid methyl ester (a neuroprotective agent). His overall research interests include: general neurology, stroke, cerebral ischemia, neuroprotection, angiogenesis, and cerebral blood flow.
MR Angiography of the Rat Brain
All images were generated from the same 3D GEPC angiography acquisition. all images are MIPs (maximum intensity projections) with the two animations created in 8º intervals. The bottom left animation is rotated around the y-axis. FOV (26x26mm), MTX (256^3), resolution (102mm), TR (56ms), TE (4.4ms) and TA (1h1m). (courtesy of Kyle Padgett, PhD)
Cardiopulmonary arrest (CA) remains one of the leading causes of death or disability in the USA. The chances of survival following CA are poor, despite fast medical emergency responses and better defibrillation techniques. The prevalent quandary in this field is the multi-factorial nature of CA: i.e. whole body ischemia, which compromises systemic blood parameters and cerebral, renal and cardiac functions, and consequent disruption of cerebral blood flow (CBF) and sympathetic over-stimulation, that results in severe and selective brain damage (i.e. neuronal cell death). Derangements of CBF occur hours after ischemia caused by acute hyperemia (increased CBF) and hypoperfusion (decreased CBF) and again one or several days after CA; there is hypoperfusion thought to be critical in CBF autoregulation detrimental to the brain.
Cardiac arrest remains one of the leading causes of death and disability in the USA. The chances of survival following cardiac arrest are poor, despite fast medical emergency responses and better defibrillation techniques. The prevalent quandary in this field is the multi-factorial nature of cardiac arrest: i.e. whole body ischemia, which compromises systemic blood parameters and cerebral, renal and cardiac function, consequently disrupts cerebral blood flow and causes selective brain damage (i.e. neuronal cell death). Derangements of cerebral blood flow can occur minutes after ischemia caused by acute hyperemia (increased cerebral blood flow) with subsequent hypoperfusion (decreased cerebral blood flow) and again 24 hrs after cardiac arrest; there is hypoperfusion both thought to be critical in cerebral blood flow autoregulation to influence neuroprotection. The importance of identifying regulatory factors that influence cerebral blood flow autoregulation and innovative neuroprotective agents in the context of cardiac arrest is paramount to change the outcomes following cardiac arrest. We are currently investigating a new vasotone regulatory mechanism, the release of palmitic acid methyl ester (PAME) (novel vasodilator1/neuroprotection agent2) derived from the superior cervical ganglion (SCG) that innervates major cerebral arteries. The SCG innervates major brain arteries such as pial, basilar, and circle of Willis and is home to PAME, which is released from the electrically stimulated SCG in the presence of arginine derivatives such as L-arginine and Nw-Nitro-L-Arginine (nitric oxide synthase inhibitor). Administration of PAME caused endothelium-independent vasodilation and increased cortical cerebral blood flow (in vivo) more potently than some nitric oxide donors. Direct application of PAME (EC50=0.19nM), but not palmitic acid (a precursor for PAME), onto the rat/rabbit thoracic aorta denuded of endothelium caused vasodilation, suggesting that methylation of palmitic acid is crucial for vasodilation1. Therefore, we are investigating the regulatory mechanism(s) involved in palmitic acid methylation to form PAME in order to gain further insights into cerebral blood flow metabolism and functional behavior outcomes. Since PAME’s release is enhanced in the presence of arginine derivatives, we are investigating protein arginine methyltransferases (PRMTs) as regulatory “switch” for the methylation of palmitic acid. Arginine methylation (via PRMTs) is a prevalent posttranslational modification that can occur in both nucleus and cytoplasm; both are thought to be involved in many disease processes. However, PRMTs have not been documented in the functional role of methylation of palmitic acid released from the sympathetic nervous system to modulate brain cerebral blood flow and metabolism that may lead to possible functional changes in normal as well as diseased states. Our main goal is to determine the regulatory mechanism(s) of vasodilation and neuroprotection of PAME derived from the sympathetic nervous system.
Cartoon illustrating cerebral sympathetic innervations from the sympathetic chain, to the SCG innervating circle of Willis crebral arteries. SCG innervation of the circle of Willis arteries is decreased in the denervated rat. Catecholamine florescence of sympathetic nerve fibers on circle of Willis rat arteries was performed following SCG decentralization and denervation. Control (no surgery) rats (A) and SCG decentralized rates (B) exhibited dense fibers while no fibers of the SCG denervated rats (C) were present. Denervation but not decentralization of the SCG drastically decreased the catecholamine fluorescence fibers. These experiments provide direct evidence of sympathetic connectivity between the sympathetic chain and the central nervous system.
Fatty acid methyl esters are inherently interesting and most of the functional aspects of fatty acid methyl esters still remain unknown. This is problematic due to the lack of specific biomarkers for fatty acids. Currently, it is not yet possible to detect the localization of a specific fatty acid due to the lack of specific radioactive or antibody labeling a specific fatty acid chain. Another major problem arises from the complexity and high variability of these fatty acids. Even if specific biomarkers do exist for PAME and SAME, the question of additional side chains and saturation (complete or incomplete saturated fatty acids) of a specific fatty acid remains problematic. Thus, currently we can only detect the presence of fatty acid methyl esters by utilizing mass spectrometry but the method cannot be used to directly determine fatty acid localization within tissue types. Our laboratory is currently developing biomarkers specific to PAME and SAME in order to better understand PAME/SAME physiology.
Gas Chromatography / Mass Spectrometry Analyses of PAME and SAME.
The x-axis illustrates retention time eluted from the column, and the y-axis is relative intensity of the compound (kCounts). GC/MS library identified the compound as PAME and SAME with Mr of 270 and 298 respectively.
The second project in my laboratory is to investigate the sympathetic nervous system as it relates to cardiac arrest. One prominent hallmark of cerebral ischemia is the inherent enhanced activity of the sympathetic nervous system due to increased norepinephrine and neuropeptide Y. The pathophysiological function of the sympathetic nervous system on ischemia-induced injury is highly complex and rather controversial. Attenuation of norepinephrine aggravated transient ischemia-induced rat brain damage, while enhanced recovery from ischemia was prevalent in the norepinephrine-depleted brain. Neuroprotection can be achieved pharmacologically by a neuropeptide Y receptor agonist under focal ischemia. On the contrary, neuropeptide Y has been reported to be associated with memory acquisition impairment. These limited studies are conflicting/controversial; therefore, we sought to delineate the pathophysiological mechanism(s) of the sympathetic nervous system after cardiac arrest. We recently reported that attenuation of the sympathetic nervous system via decentralization (DEC, interruption of preganglionic fibers) of the superior cervical ganglion can decrease asphyxial cardiac arrest (ACA)-induced hypoperfusion, afford neuroprotection, and reverse cardiac arrest-induced working memory deficits. DECpre+ACA decreased neuropeptide Y mRNA and protein levels suggesting that attenuation of the sympathetic nervous system during cardiac arrest can decrease neuropeptide Y levels. Our goal is to delineate neural pathways and neurotransmitter(s) involved with the benefits of sympathetic nervous system attenuation during cardiac arrest by inhibition of neuropeptide Y release via presynaptic neuropeptide Y-2 agonist (PYY3-36).
We are currently investigating the modulation of neuropeptide Y. We hypothesize that a decrease in neuropeptide Y can inhibit the excessive activation of the sympathetic nervous system caused by CA to alleviate cerebral blood flow derangements, prevent neuronal cell death and neurological deficits. These studies are ongoing and will not only highlight the importance of SNS modulation to cerebral ischemia, but also seek to clarify the controversial studies and conflicting reports to further set the stage for future studies. The innovation of this proposal is attenuation but not enhancement of the sympathetic nervous system is actually beneficial to maintain cerebral blood flow, promote neuronal survival and functional recovery after cardiac arrest. In addition, the use of neuropeptide Y modulation therapy via (PYY3-36) can prove to be beneficial to combat against ischemia-related neuronal deficits. Investigating the function of the sympathetic nervous system after cardiac arrest in the brain can lead to novel therapies and allow for further exploration of possible mechanism(s) (i.e. neural networks) and provide a basic understanding in the brain via the sympathetic nervous system highway, as it relates to ischemia, to formulate new translatable therapeutic interventions.
My inherent interest in Project 1 with regards to palmitic acid methyl ester lead me to the field of fatty acid biology. Fatty acids are interesting and challenging in that therapeutic targets are unclear. Much of therapeutics target protein/peptides. However, as a scientific community, we are ignoring a whole class of compounds inherent to biological systems that need further investigation. I currently have multiple consultation contracts with companies such as Sancilio and Company, Lipid Biologics, and New Health Sciences. One of the barriers utilizing docosahexaenoic acid/Omega-3 as a therapy is the inherent poor bioavailability after ingestion of these polyunsaturated fatty acids. Pharmaceutical firms including Sancilio and Company are racing to the finish to design novel excipients that have better absorption and bioavailability.
We currently have a joint venture with Sancilio and Company to study the effects of sickle cell disease with regards to brain circulation utilizing docosahexaenoic acid as a therapeutic. Docosahexaenoic acid is a polyunsaturated fatty acid and has been implicated in various therapeutic. We are currently determining if chronic docosahexaenoic acid treatment will enhance cerebral blood flow, systemic blood flow (i.e. increase in red blood cell velocity) and also red blood cell flux. We use novel in vivo imaging of the cerebral microvessels via intra-vital two-photon laser scanning microscopy under hypoxic conditions. This is due to the fact that vaso-occlusive crisis in sickle cell patients normally occur under hypoxia.
- Wu CY, Couto E Silva A, Citadin CT, Clemons GA, Acosta CH, Knox BA, Grames MS, Rodgers KM, Lee RH, Lin HW. Palmitic acid methyl ester inhibits cardiac arrest-induced neuroinflammation and mitochondrial dysfunction. Prostaglandins Leukot Essent Fatty Acids. 2021 Feb;165:102227. doi: 10.1016/j.plefa.2020.102227. Epub 2020 Dec 17. PubMed PMID: 33445063; NIHMSID:NIHMS1661898.
- Lee RH, Grames MS, Wu CY, Lien CF, Couto E Silva A, Possoit HE, Clemons GA, Citadin CT, Neumann JT, Pastore D, Lauro D, Della-Morte D, Lin HW. Upregulation of serum and glucocorticoid-regulated kinase 1 exacerbates brain injury and neurological deficits after cardiac arrest. Am J Physiol Heart Circ Physiol. 2020 Nov 1;319(5):H1044-H1050. doi: 10.1152/ajpheart.00399.2020. Epub 2020 Sep 18. PubMed PMID: 32946263.
- Chen PY, Wu CY, Clemons GA, Citadin CT, Couto E Silva A, Possoit HE, Azizbayeva R, Forren NE, Liu CH, Rao KNS, Krzywanski DM, Lee RH, Neumann JT, Lin HW. Stearic acid methyl ester affords neuroprotection and improves functional outcomes after cardiac arrest. Prostaglandins Leukot Essent Fatty Acids. 2020 Aug;159:102138. doi: 10.1016/j.plefa.2020.102138. Epub 2020 May 23. PubMed PMID: 32663656.
- Wu CYC, Lopez-Toledano MA, Daak AA, Clemons GA, Citadin CT, Sancilio FD, Rabinowicz AL, Minagar A, Neumann JT, Lee RHC, Lin HW. SC411 treatment can enhance survival in a mouse model of sickle cell disease. Prostaglandins Leukot Essent Fatty Acids. 2020 Jul;158:102110. doi: 10.1016/j.plefa.2020.102110. Epub 2020 May 3. PubMed PMID: 32447175.
- Couto E Silva A, Wu CY, Citadin CT, Clemons GA, Possoit HE, Grames MS, Lien CF, Minagar A, Lee RH, Frankel A, Lin HW. Protein Arginine Methyltransferases in Cardiovascular and Neuronal Function. Mol Neurobiol. 2020 Mar;57(3):1716-1732. doi: 10.1007/s12035-019-01850-z. Epub 2019 Dec 10. Review. PubMed PMID: 31823198; PubMed Central PMCID: PMC7062579.
- Lee RH, Couto E Silva A, Possoit HE, Lerner FM, Chen PY, Azizbayeva R, Citadin CT, Wu CY, Neumann JT, Lin HW. Palmitic acid methyl ester is a novel neuroprotective agent against cardiac arrest. Prostaglandins Leukot Essent Fatty Acids. 2019 Aug;147:6-14. doi: 10.1016/j.plefa.2018.11.011. Epub 2018 Nov 23. PubMed PMID: 30514597; PubMed Central PMCID: PMC6533160.
- Wu CYC, Lerner FM, Couto E Silva A, Possoit HE, Hsieh TH, Neumann JT, Minagar A, Lin HW, Lee RHC. Utilizing the Modified T-Maze to Assess Functional Memory Outcomes After Cardiac Arrest. J Vis Exp. 2018 Jan 5;(131). doi: 10.3791/56694. PubMed PMID: 29364254; PubMed Central PMCID: PMC5908446.
- Lee RH, Couto E Silva A, Lerner FM, Wilkins CS, Valido SE, Klein DD, Wu CY, Neumann JT, Della-Morte D, Koslow SH, Minagar A, Lin HW. Interruption of perivascular sympathetic nerves of cerebral arteries offers neuroprotection against ischemia. Am J Physiol Heart Circ Physiol. 2017 Jan 1;312(1):H182-H188. doi: 10.1152/ajpheart.00482.2016. Epub 2016 Nov 18. PubMed PMID: 27864234.
Invited Book Chapters
- Wu CY, Lee RHC, Lee MHH, Couto e Silva A, Hsieh THH, Possoit H, Brackett AL, Lin HW. (2017) Role of Neuroinflammation in Pathophysiology of Traumatic Brain Injury. In: Alireza Minagar (Ed.), Neuroinflammation (2nd ed.). Amsterdam, Netherlands: Elsevier Publishers Company. (Corresponding author)
- Lee RHC, Wilkins CS, Couto e Silva, A, Valido SE, Wu, CY, Lin HW. (2014) Fatty Acids in Vascular Health. In: Lucas F. Porto (Ed.), Palmitic Acid: Occurrence, Biochemistry and Health Effects (1st ed.). Hauppauge, NY: Nova Science Publishers. (Corresponding author)
- Dave KR, Thompson JW, Neumann JT, Perez-Pinzon MA, Lin HW. (2013) Neurovascular mechanisms of ischemia tolerance against brain injury. In: EH Lo, J Lok, MM Ning, MJ Whalen (Eds.), Vascular Mechanisms in CNS Trauma (1st ed.). NY, NY: Springer Publishing Company.
- Narayanan SV, Morris-Blanco, KC, Perez-Pinzon MA, Lin HW. (2012). Ischemic preconditioning-mediated signaling pathways leads to tolerance against cerebral ischemia. In JM Gidday, MA Perez-Pinzon, & JH Zhang (Eds.), Innate Neuroprotection for Stroke (1st ed.). NY, NY: Springer Publishing Company. (Corresponding author)
- Dave KR, Lin HW, Perez-Pinzon MA. (2012). Tolerance against global cerebral ischemia: experimental strategies, mechanisms and clinical applications. In JM Gidday, MA Perez-Pinzon, & JH Zhang (Eds.), Innate Neuroprotection for Stroke (1st ed.). NY, NY: Springer Publishing Company.
We welcome applicants from different universities/colleges to join our lab. We expect applicants to be highly motivated and interested in the science. There is space available for outstanding applicants to participate in various exciting research both in vivo and in vitro projects. If you are interested in joining our research group, please email Dr. Lin at email@example.com.
Title: Vascular Regulatory Mechanisms of Palmitic Acid Methyl Ester
Title: Regulation of the sympathetic nervous system in cerebral ischemia
Louisiana State University Research Council
Title: Ischemic macrophage polarization
Duration: 1/1/21- 12/31/21
Title: Serum/glucocorticoid regulated kinase 1 in cerebral ischemia
Role: Mentor to Reggie Lee, PhD
Title: Neuropeptide Y-mediated Neuroprotection
Role: Sponsor to Celeste Wu, PhD
LSU Health Shreveport
Department of Neurology
1501 Kings Hwy
Shreveport, LA 71103