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Pin-Lan Li, M.D., Ph.D. |
Education: M.D. Yichang Medical College, China, 1975, Ph.D. University of Heidelberg, Germany, 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 last 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 feedforward 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 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.
Zhang AY, F Yi, G Zhang, E Gulbins, PL Li. Lipid rafts clustering and
redox signaling platform formation in coronary arterial endothelial cells.
Hypertension 47: 74-80, 2006. (Editorial commentary on Hypertension
47: 16-18, 2006).
Zhang G, EG Teggetz, AY Zhang, MJ Koeberl, F Yi, L Chen, PL Li. Cyclic
ADP-ribose-mediated Ca2+ signaling in mediating endothelial nitric oxide
production in bovine coronary arteries. Am J Physiol Heart Circ Physiol
290: H1172-H1181, 2006.
Zhang F, G Zhang, AY Zhang, MJ Koeberl, EL Wallander, PL Li. Production of
NAADP and its role in Ca2+ mobilization associated with lysosome in
coronary arterial myocytes. Am J Physiol Heart Circ Physiol
291(1):H274-282, 2006.
Yi F, AY Zhang, NJ Li, RW Muh, Fillet M, Renert AF, PL Li. Inhibition of
ceramide/redox signaling pathway blocks glomerular injury in
hyperhomocysteinemic rats, Kidney Int 70(1):88-96, 2006.
Li N, RW Muh, PL Li. Hyperhomocysteinemia associated with decreased renal
transulphuration activity in Dahl S hypertensive rats. Hypertension
47(6):1094-1100, 2006.
Zhang G, F Zhang, Muh R, F Yi, K Chalupsky, H Cai, PL Li. Autocrine/paracrine
pattern of superoxide production through NAD(P)H Oxidase in coronary
arterial myocytes. Am J Physiol Heart Circ Physiol 292:H483-495,
2007.
Li N, F Yi, EA dos Santos, DK Donley, PL Li. Role of renal medullary heme
oxygenase in the regulation of pressure natriuresis and arterial blood
pressure. Hypertension 49(1):148-154, 2007. (Editorial commentary
on Hypertension 49: 23-24, 2007).
Yi F, EA dos Santos, M Xia, Q-Z Chen PL Li, N Li. Podocyte injury and
glomerulosclerosis in hyperhomocysteinemic rats. Am J Nephrol
27:262–268, 2007.
Zhang AY, F Yi, S Jin, M Xia, QZ Chen, E Gulbins and PL Li. Acid
sphingomyelinase and Its redox amplification in formation of lipid raft
redox signaling platforms in endothelial cells. Antioxid & Red Signal
9(7):817-828, 2007.
Li PL and E Gulbins. Lipid rafts and redox signaling. Antioxid & Redox
Signal 9(9): 1411-1416 2007.
Zhang F, PL Li. Reconstitution and characterization of a nicotinic acid
adenine dinucleotide phosphate (NAADP)-sensitive Ca2+ release
channel from liver lysosomes of rats. J Biol Chem.
282(35):25259-25269, 2007.
Jin Si, Y Zhang, F Yi, PL Li. Critical role of lipid raft redox signaling
platforms in endostatin-induced coronary endothelial dysfunction.
Arterioscler Thromb Vasc Biol 28:485-490, 2008.
Li N, L Chen, F Yi, M Xia, PL Li. Salt-Sensitive Hypertension Induced by
Decoy of Transcription Factor Hypoxia-inducible factor-1α in the Renal
Medulla. Circ Res. 102(9):1101-1108, 2008.
Jin S, F Yi, S Jia, F Zhang, C Evans, PL Li. Lysosomal targeting and
trafficking of acid sphingomyelinase to lipid raft platforms in coronary
endothelial cells. Arterioscler Thromb Vasc Biol. 28:2056-2062,
2008.
Jia SJ, Jin S, Zhang F, Yi F, PL Li. Formation and Function of Ceramide-Enriched
Membrane Platforms with CD38 during M1-Receptor Stimulation in Bovine
Coronary Arterial Myocytes. Am J Physiol-Heart Circ Physiol.
295(4):H1743-52 2008.