Director for Hypertension and Kidney Research Arthur and Margaret Glasgow Chair

Department: Department of Pharmacology and Toxicology

Phone: (804) 828-4793

Fax: (804) 828-2117

Email: pin-lan.li@vcuhealth.org

Address/Location:
Molecular Medicine Research Building, Room 3050
1220 East Broad Street
Box 980613
Richmond, Virginia

Education

• Yichang Medical College, China, M.D., 1975
• University of Heidelberg, Germany, Ph.D., 1992

Research interests

• Cardiovascular pharmacology

Research in my laboratory mainly deals with the cell and molecular regulation of coronary circulation and pathogenesis of renal glomerular injury associated with hyperhomocysteinemia and hypertension. Some specific projects and approaches are as follows:

Transmembrane signaling mechanisms in coronary endothelial cells – lipid rafts and molecular trafficking
Beyond enzyme-mediated amplification in various cell-signaling cascades, we are now exploring another important mechanism that massively amplifies the signals when ligands bind to their receptors. This mechanism is characterized by clustering of membrane lipid microdomains (lipid rafts) and formation of different signaling platforms. In this process, many receptors and signaling molecules aggregate on stimulation, resulting in a very high density of the receptors and other signaling molecules in certain areas of cell membrane to form signaling platforms, which transmit and amplify the signals from receptor activation. A major focus of research is now on defining the mechanism mediating the formation of lipid rafts-associated redox signaling platforms in coronary endothelial cells and exploring the physiological and pathological significance of these redox signaling platforms. Many advanced cell and molecular approaches have been used such as confocal microscopy, fluorescence resonance energy transfer (FRET), electron spin resonance (ESR) spectrometry, high-speed fluorescence imaging, real-time PCR, RNA interference, somatic gene manipulations and genetic engineered animal models.

Novel intracellular second messengers, cadpr in coronary arterial myocytes 
Cyclic ADP-ribose (cADPR) serves as a second messenger to mediate intracellular Ca2+ mobilization independent of IP3 signaling pathway in different tissues or cells. Over the past 10 years, we have demonstrated that cADPR induces Ca2+ release from intracellular stores of coronary arterial smooth muscle cells and that inhibition of cADPR production results in the relaxation of coronary arteries. This cADPR-mediated Ca2+ signaling pathway is now considered as an important target in a redox feed-forward regulation in vascular smooth muscle. When vascular smooth muscle cells are activated by different vasoconstrictor stimuli, an NADPH oxidase-associated redox signaling amplification is also initiated. In this process, NADH is used to produce superoxide and NAD+, which could result in cADPR increase since NAD+ is a substrate of ADP-ribosyl cyclase and superoxide can activate this cADPR producing enzyme. cADPR mobilizes intracellular Ca2+, enhancing vasoconstrictor response. Various approaches used in these projects include: high-speed fluorescence imaging of intracellular Ca2+, superoxide and other redox molecules, patch clamp, FRET, video microscopy of small artery functionality, RNA interference, ELISA, ESR, gene overexpression and genetically engineered animal models.

Characteristics and function of a novel lysosomal ca2+ release channel – trp-ml1 in arterial myocytes
Lysosomes are recently demonstrated as an intracellular Ca2+ store where Ca2+ can be mobilized to produce cellular physiological responses. However, little is known about how Ca2+ is released from this store in response to different agonists or stimuli. We have provided the first experimental evidence demonstrating that a Ca2+ release channel is present in lysosomes and that its identity may be mucolopin-1, a transient receptor potential (TRP) channel, namely, TRP mucolipin 1 (TRP-ML1). Given the action of nicotinic acid adenine dinucleotide phosphate (NAADP) stimulating lysosomal Ca2+ release, a hypothesis is that TRP-ML1 may be an NAADP-sensitive Ca2+ release channel in lysosomes of coronary arterial smooth muscle cells. This TRP-ML1 channel may mediate local Ca2+ bursts from lysosomes and leads to a two-phase Ca2+ release that participates in the vasomotor response of coronary arteries to agonists. We are now testing this hypothesis using different physiological, biochemical and molecular approaches, including ion channel reconstitution, lipid bilayer channel recording, patch clamp, high-speed fluorescence imaging, HPLC, ELISA, confocal and electron microscopy, RNA interference, gene mutation and overexpression.

Molecular mechanisms of hyperhomocysteinemia-induced arteriosclerosis and glomerular sclerosis
Hyperhomocysteinemia (hHcys) is a novel risk factor or pathogenic factor for atherosclerosis and glomerular sclerosis associated with hypertension. We are now investigating the molecular mechanisms mediating the pathogenic action of homocysteine (Hcys) in the development of glomerular sclerosis with a major focus on the contribution of guanine nucleotide exchange factors (GEF). The hypothesis to be tested is that the GEF-Vav as a target signaling molecule of Hcys activates Rac-NADPH oxidase and thereby triggers the cascade of glomerular injury and sclerosis including local oxidative stress, podocytes dysfunction, extracellular matrix deposition and fibrosis. A series of cellular, molecular and whole animal experimental approaches are used to test this hypothesis, such as pull-down assay of Rac GTPase, ESR, Western blot analysis, real-time PCR, RNA interference, gene overexpression, dominant active or negative gene mutants, in vivo molecular imaging, isolated glomeruli approaches, HPLC, immunocytochemistry and whole animal monitoring of arterial pressure and renal functions.

Selected publications

1. Xia M, Abais JM, Boini KM, Li PL. Characterization and activation of NLRP3 inflammasomes in the renal medulla in mice. Kidney Blood Press Res. 41:208-221, 2016. PMCID: PMC4824620.
2. Boini KM, Xia M, Koka S, Gehr T, Li PL. Instigation of NLRP3 inflammasome activation and glomerular injury in mice on the high fat diet: Role of acid sphingomyelinase gene. Oncotarget. 7:19031-19044, 2016. PMCID: PMC4951349
3. Chen Y, Yuan M, Xia M, Wang L, Zhang Y, Li PL. Instant membrane resealing in NLRP3 inflammmasome activation of endothelial cells. Front Biosci (Landmark Ed). 21:635-650, 2016. PMCID: PMC5507337
4. Bao JX, Zhang QF, Wang M, Boini KM, Gulbins E, Zhang Y, Li PL. Implication of CD38 gene in autophagic degradation of collagen I in mouse coronary arterial myocytes. Front Biosci. (Landmark Ed), 22:558-569, 2017. PMCID: PMC5509348
5. Conley SM, Abais-Batted JM, Yuan X, Zhang Q, Boini KM, Li PL. Contribution of guanine nucleotide exchange factor vav2 to NLRP3 inflammasome activation in mouse podocytes during hyperhomcysteinemia. Free Radic Biol Med. 106:236-244, 2017. PMCID: PMC5423457
6. Li G, Chen Z, Bhat OM, Zhang Q, Abais-Batad J, Conley SM, Ritter J, Li PL. NLRP3 inflammasome as a novel target for docosahexaenoic acid metabolites to abrogate glomerular injury. J Lipid Res. 58:1080-1090, 2017. PMCID: PMC5454504
7. Koka S, Xia M, Chen Y, Bhat OM, Yuan X, Boini KM, Li PL. Endothelial NLRP3 inflammasome activation and arterial neointima formation associated with acid sphingomyelinase during hypercholesterolemia. Redox Biol. 13:336-344, 2017. PMCID: PMC5479959
8. Yuan X, Wang L, Bhat OM, Lohner H, Li PL. Differential effects of short chain fatty acids on endothelial Nlrp3 inflammasome activation and neointima formation: Antioxidant action of butyrate. Redox Biol. 16:21-31, 2018. PMCID: PMC5842312
9. Bhat OM, Yuan X, Li G, Lee R, Li PL. Sphingolipids and redox signaling in renal regulation and chronic kidney diseases. Antioxid Redox Signal. 28:1008–1026, 2018. PMCID: PMC5849286
10. Li PL, Gulbins E. Bioactive lipids and redox signaling: Molecular mechanism and disease pathogenesis. Antioxid Redox Signal. 28:911–915 2018. PMCID: PMC5849277
11. Li G, Zhang Q, Hong J, Ritter JK, Li PL: Inhibition of pannexin-1 channel activity by adiponectin in podocytes: Role of acid ceramidase activation. BBA-Mol Cell Biol Lipids. 1863:1246-1256, 2018. PMCID: PMC618094
12. Yuan X, Bhat OM, Meng N, Lohner H, Li PL. Protective role of autophagy in Nlrp3 inflammasome activation and medial thickening of mouse coronary arteries. Am J Pathol. 188:2948-2959, 2018. PMCID: PMC6334256
13. Yuan X, Bhat OM, Lohner H, Li N, Zhang Y, Li PL. Inhibitory effects of growth differentiation factor 11 on autophagy deficiency-induced dedifferentiation of arterial smooth muscle cells. Am J Physiol Heart Circ Physiol. 316:H345-H356, 2019. PMCID: PMC639738
14. Hong J, Bhat OM, Li G, Dempsey SK, Zhang Q, Ritter JK, Li W, Li PL. Lysosomal regulation of extracellular vesicle excretion during D-Ribose-induced NLRP3 inflammasome activation in podocytes. BBA-Mol Cell Res. 1866:849-860, 2019. PMID: 30771382
15. Zhang Q, Conley SM, Li G, Yuan X, Li PL. Rac1 GTPase inhibition blocked podocyte injury and glomerular sclerosis during hyperhomocysteinemia via suppression of nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 inflammasome activation. Kidney Blood Press Res. 2019 Jul 2:1-20. doi: 10.1159/000500457. [Epub ahead of print]
16. Li G, Huang D, Hong J, Bhat OM, Yuan X, Li PL. Control of lysosomal TRPML1 channel activity and exosome release by acid ceramidase in mouse podocytes. Am J Physiol-Cell Physiol. 2019 Jul 3. doi: 10.1152/ajpcell.00150.2019. [Epub ahead of print]

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