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Pin-Lan Li, M.D., Ph.D.

Pin-Lan Li, M.D., Ph.D.

Pin-Lan Li, MD, PhD
Professor and Vice Chair
Department of Pharmacology & Toxicology
Director for Hypertension and Kidney Research
Arthur and Margaret Glasgow Chair
Virginia Commonwealth University
MMRB, 3rd Floor, Room 3050
1220 East Broad Street
P.O.Box 980613
Richmond, VA 23298-0613

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

Research interests:

Cardiovascular-renal 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.

Selected publications:

Xu M, Zhang Y, Xia M, Li XX, Ritter JK, Zhang F, Li PL. NAD(P)H oxidase-dependent intracellular and extracellular O2.- production in coronary arterial myocytes from CD38 knockout mice. Free Rad Biol Med. 52(2):357-65, 2012. PMCID:PMC3253214

Han WQ, Xia M, Xu M, Boini KM, Ritter JK, Li NJ, Li PL. Lysosome fusion to the cell membrane is mediated by the dysferlin C2A domain in coronary arterial endothelial cells. J Cell Sci. 125(Pt 5):1225-34, 2012. PMCID:PMC3324581

Xu M, Xia M, Li XX, Han WQ, Boini KM, Zhang F, Zhang Y, Ritter JK, Li PL. Requirement of translocated lysosomal V1 H+-ATPase for activation of membrane acid sphingomyelinase and raft clustering in coronary endothelial cells. Mol Biol Cell. 23(8):1546-1557, 2012. PMCID: PMC3327313

Zhang C, Boini KM, Xia M, Abais JM, Liu QL, Li PL. Activation of Nod-like receptor protein 3 inflammasomes turns on podocyte injury and glomerular sclerosis in hyperhomocysteinemia. Hypertension. 60(1):154-162, 2012. PMCID (In process)

Zhu Q, Liu M, Han WQ, Li PL, Wang Z, Li N. Overexpression of HIF prolyl-Hydoxylase-2 transgene in the renal medulla induced a salt-sensitive hypertension. J Cell Mol Med. 16(11):2701-2707, 2012. PMCID: PMC3461349.

Ritter, JK, Li C, Xia M, Poklis JL, Lichtman AH, Abdullah RA, Dewey WL, Li PL. Production and actions of the anandamide metabolite, prostamide E2, in the renal medulla. J Pharmacol Exp Ther. 342(3):770-779, 2012. PMCID: PMC3422528.

Ritter JK, Fang Y, Xia M, Li PL, Dewey WL. Contribution of acid sphingomyelinase in the periaqueductal gray region to morphine-induced analgesia in mice. Neuroreport.  23(13): 780-785, 2012. PMCID: PMC3732375

Boini KM, Xia M, Xu M, Li C, Li PL. Acid sphingomyelinase gene knockout ameliorates hyperhomocysteinemic glomerular injury in mice lacking cystathionine β-synthase. PLoS ONE. 7(9):e45020, 2012. 

Abais JM, Zhang C, Xia M, Liu Q, Gehr T, Boini KM, Li PL. NADPH oxidase-mediated triggering of inflammasomes activation in mouse podocytes and glomeruli during hyperhomocysteinemia. Antioxid Redox Singal. 18(13):1537-1548, 2013. PMCID: PMC3613176.

Li X, Han WQ, Boini KM, Xia M, Zhang Y, Li PL. TRAIL death receptor 4 signaling via lysosome fusion and membrane raft clustering in coronary arterial endothelial cells: evidence from ASM knockout mice. J Mol Med. 91:25-36, 2013. PMCID: PMC3537912

Xiong J, Xia M, Yi F, Abais JM, Li N, Boini KM, Li PL. Regulation of renin release via cyclic ADP-ribose-mediated signaling: Evidence from mice lacking CD38 gene. Cell. Physiol. Biochem. 31(1):44-55, 2013. PMCID: PMC3753399

Xu M, Li X, Walsh SW, Zhang Y, Abais JM, Boini KM, Li PL. Intracellular Two-phase Ca2+ Release and Apoptosis Controlled by TRP-ML1 Channel Activity in Coronary Arterial Myocytes.  Am J Physiol Cell Physiol. 304(5):C458-C466, 2013. PMCID:PMC3602645.

Wei YM, Li X, Xiong J, Abais JM, Xia M, Boini KM, Zhang Y, Li PL. Attenuation by statins of membrane raft-redox signaling in coronary arterial endothelium, J Pharmacol Exp Ther. 345(2):170-179, 2013. PMCID:PMC3629800

Yang Zhang, Li PL. Cross-Talk between ceramide and redox signaling: Implications in endothelial dysfunction and renal disease.  In: Ceramide in Health and Disease. Handb Exp Pharmacol. 216:171-197, 2013. PMCID (book chapter) Ed: Erich Gulbins

Wei YM, Li X, Xu M, Abais JM, Chen Y, Riebling CR, Boini KM, Li PL, Zhang Y. Enhancement of autophagy by simvastatin through inhibition of Rac1-mTOR signaling pathway in coronary arterial myocytes statin autophagy. Cell Physiol Biochem. 31:925-937, 2013. PMCID: PMC3753088

Xu M, Li X, Ritter JK, Abais JM, Zhang Y, Li PL. Contribution of NADPH Oxidas