Louis J. Ignarro, Ph.D.
Work Email Address:
Office Phone Number:
269 South Beverly Drive
Beverly Hills, CA 90212
|Member, Brain Research Institute|
|Professor Emeritus, Molecular & Medical Pharmacology|
NO is one of the simplest molecules in nature but is synthesized by a complex enzymatic process. NO synthase is a homodimeric flavo-hemoprotein that catalyzes the 5-electron oxidation of L-arginine to NO + L-citrulline. This enzymatic reaction is similar to that catalyzed by the cytochrome P450 system, and requires numerous cofactors including calmodulin, NADPH, flavins, heme and tetrahydrobiopterin. NO synthase exists as three different isoforms; endothelial, neuronal and inducible. Endothelial and neuronal NO synthase are constitutively present in select cell types and is activated by intracellular calcium, which promotes the binding of calmodulin to the enzyme and thereby activates it. The inducible NO synthase already has calmodulin tightly bound as a subunit and, therefore, requires no calcium for enzyme activation; it is already activated as it is being synthesized from its mRNA. NO is a very small, lipophilic, readily diffusible, chemically unstable molecule with a very short half-life (seconds) and produces effects immediately and locally.
NO elicits physiological (vasodilation, anti-platelet effects, neurotransmitter functions) and pathophysiological actions (septic shock, acute and chronic inflammation, destruction of invading bacteria, viruses and tumor cells). Two different constitutively present isoforms of NO synthase (endothelial and neuronal NOS) are responsible for biosynthesis of small physiologically important amounts of NO. Such small amounts of NO are completely non-cytotoxic. An inducible isoform of NO synthase, which a distinct gene product from the constitutive isoforms, is responsible for high-output production of NO. Generation of large amounts of NO is associated with cytotoxicity and pathophysiology. Examples include induction of NO synthase in vascular smooth muscle resulting in profound vasorelaxation and hypotension, the characteristics of endotoxin shock; induction of NO synthase in brain microglia and astrocytes thereby resulting in production of large amounts of NO which permeate nearby oligodendrocytes resulting in impaired myelin production, the hallmark feature of multiple sclerosis; induction of NO synthase in joint tissues resulting in acute and chronic inflammation, characteristic signs of arthritic disease.
Research efforts in this laboratory are directed toward better understanding the factors that influence NO production and cytotoxicity. Studies are focused on the transcriptional regulation of inducible NO synthase and the involvement of NF-kB and other transcription factors in the inducible expression of the NO synthase gene. Separate projects focus on the mechanism by which oxidative stress triggers activation of NF-kB and induction of host-defense proteins. The relationship between oxidative stress and signal transduction in inducible gene expression is a major area of current focus. Additional projects address the roles of phosphorylation and proteolysis in gene transcription. Pertaining to the cytotoxic actions of NO, studies focus on the chemistry of NO as a reactive species with iron and copper, and how such reactivity alters cell function. The double-edged role of NO as both a protective species and deleterious species is intriguing and under investigation in various cell types including tumor cells as NO appears to have potent tumoricidal activity.
Additional specific aims focus on (1) co-induction of NO synthase and arginase and arginine transporters in macrophages and vascular cells to understand the factors affecting arginine availability for NO synthase catalyzed NO production; (2) mechanisms by which certain combinations of lipopolysaccharide plus cytokines cause rapidly developing death in certain cell types but not others; (3) mechanisms by which NO injures target cells and microorganisms without injuring cells that produce NO; (4) elucidation of the role of tetrahydrobiopterin as a cofactor for NO synthase; (5) elucidation of the mechanism by which NO causes a negative feedback effect on NO synthase to inhibit its own synthesis; (6) elucidation of the mechanism by which NO activates guanylate cyclase, the enzyme that catalyzes the formation of cyclic GMP, an important second messenger that mediates the physiological actions of NO; (7) determination of the factors that affect the transcriptional expression and posttranslational modifications of guanylate cyclase.
This laboratory made the original observations that NO is a vasodilator (1979) and inhibitor of platelet aggregation (1981), that NO elicits its biological actions via the second messenger cyclic GMP (1979-1981), that NO activates guanylate cyclase by heme-dependent mechanisms (1982), that the endothelium-derived relaxing factor is NO, that NO is the neurotransmitter in nonadrenergic-noncholinergic neurons innervating the erectile tissue of the penis and is responsible for penile erection (1990), that NO is a negative feedback modulator of NO synthase (1992), and that aspirin and related drugs interfere with the inducible expression of the NO synthase gene (1995).
Therefore, this laboratory is committed to continued and persistent research into the biology and chemistry of NO.
Napoli Claudio, Paolisso Giuseppe, Casamassimi Amelia, Al-Omran Mohammed, Barbieri Michelangela, Sommese Linda, Infante Teresa, Ignarro Louis J Effects of nitric oxide on cell proliferation: novel insights. Journal of the American College of Cardiology. 2013; 62(2): 89-95.
Kwon Kyoung Ja, Kim Jung Nam, Kim Min Kyeong, Kim Su Young, Cho Kyu Suk, Jeon Se Jin, Kim Hahn Young, Ryu Jong Hoon, Han Sun-Young, Cheong Jae Hoon, Ignarro Louis J, Han Seol-Heui, Shin Chan Young Neuroprotective effects of valproic acid against hemin toxicity: possible involvement of the down-regulation of heme oxygenase-1 by regulating ubiquitin-proteasomal pathway. Neurochemistry international. 2013; 62(3): 240-50.
de Nigris Filomena, Rienzo Monica, Sessa Marcella, Infante Teresa, Cesario Elena, Ignarro Louis J, Al-Omran Mohammed, Giordano Antonio, Palinski Wulf, Napoli Claudio Glycoxydation promotes vascular damage via MAPK-ERK/JNK pathways. Journal of cellular physiology. 2012; 227(11): 3639-47.
Zheng Min, Kim Seul-Ki, Joe Yeonsoo, Back Sung Hoon, Cho Hong R, Kim Hong Pyo, Ignarro Louis J, Chung Hun-Taeg Sensing endoplasmic reticulum stress by protein kinase RNA-like endoplasmic reticulum kinase promotes adaptive mitochondrial DNA biogenesis and cell survival via heme oxygenase-1/carbon monoxide activity. FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 2012; 26(6): 2558-68.
Fukuto Jon M, Carrington Samantha J, Tantillo Dean J, Harrison Jason G, Ignarro Louis J, Freeman Bruce A, Chen Andrew, Wink David A Small molecule signaling agents: the integrated chemistry and biochemistry of nitrogen oxides, oxides of carbon, dioxygen, hydrogen sulfide, and their derived species. Chemical research in toxicology. 2012; 25(4): 769-93.
Zhang Rong, Jack Gregory S, Rao Nagesh, Zuk Patricia, Ignarro Louis J, Wu Benjamin, RodrÃguez Larissa V Nuclear fusion-independent smooth muscle differentiation of human adipose-derived stem cells induced by a smooth muscle environment. Stem cells (Dayton, Ohio). 2012; 30(3): 481-90.
Ma Limin, Yang Yijun, Sikka Suresh C, Kadowitz Philip J, Ignarro Louis J, Abdel-Mageed Asim B, Hellstrom Wayne J G Adipose tissue-derived stem cell-seeded small intestinal submucosa for tunica albuginea grafting and reconstruction. Proceedings of the National Academy of Sciences of the United States of America. 2012; 109(6): 2090-5.
Meldrum David R, Gambone Joseph C, Morris Marge A, Meldrum Donald A N, Esposito Katherine, Ignarro Louis J The link between erectile and cardiovascular health: the canary in the coal mine. The American journal of cardiology. 2011; 108(4): 599-606.
Kwon Kyoung Ja, Cho Kyu Suk, Lee Sung Hoon, Kim Jung Nam, Joo So Hyun, Ryu Jong Hoon, Ignarro Louis J, Han Seol-Heui, Shin Chan Young Regulation of tissue plasminogen activator/plasminogen activator inhibitor-1 by hydrocortisone in rat primary astrocytes. Journal of neuroscience research. 2011; 89(7): 1059-69.
Matsui-Hirai Hisako, Hayashi Toshio, Yamamoto Seiji, Ina Koichiro, Maeda Morihiko, Kotani Hitoshi, Iguchi Akihisa, Ignarro Louis J, Hattori Yuichi Dose-dependent modulatory effects of insulin on glucose-induced endothelial senescence in vitro and in vivo: a relationship between telomeres and nitric oxide. The Journal of pharmacology and experimental therapeutics. 2011; 337(3): 591-9.
Napoli Claudio, Giordano Antonio, Casamassimi Amelia, Pentimalli Francesca, Ignarro Louis J, De Nigris Filomena Directed in vivo angiogenesis assay and the study of systemic neoangiogenesis in cancer. International journal of cancer. Journal international du cancer. 2011; 128(7): 1505-8.
Napoli Claudio, Hayashi Toshio, Cacciatore Francesco, Casamassimi Amelia, Casini Costanza, Al-Omran Mohammed, Ignarro Louis J Endothelial progenitor cells as therapeutic agents in the microcirculation: an update. Atherosclerosis. 2011; 215(1): 9-22.
Kwon Kyoung Ja, Kim Jung Nam, Kim Min Kyeong, Lee Jongmin, Ignarro Louis J, Kim Hee-Jin, Shin Chan Young, Han Seol-Heui Melatonin synergistically increases resveratrol-induced heme oxygenase-1 expression through the inhibition of ubiquitin-dependent proteasome pathway: a possible role in neuroprotection. Journal of pineal research. 2011; 50(2): 110-23.
Kim Ji Woon, Lee Sung Hoon, Ko Hyun Myung, Kwon Kyoung Ja, Cho Kyu Suk, Choi Chang Soon, Park Jin-Hee, Kim Hahn Young, Lee Jongmin, Han Seol-Heui, Ignarro Louis J, Cheong Jae Hoon, Kim Won-Ki, Shin Chan Young Biphasic regulation of tissue plasminogen activator activity in ischemic rat brain and in cultured neural cells: essential role of astrocyte-derived plasminogen activator inhibitor-1. Neurochemistry international. 2011; 58(3): 423-33.
Meldrum David R, Gambone Joseph C, Morris Marge A, Ignarro Louis J A multifaceted approach to maximize erectile function and vascular health. Fertility and sterility. 2010; 94(7): 2514-20.
de Nigris Filomena, Crudele Valeria, Giovane Alfonso, Casamassimi Amelia, Giordano Antonio, Garban Hermes J, Cacciatore Francesco, Pentimalli Francesca, Marquez-Garban Diana C, Petrillo Antonella, Cito Letizia, Sommese Linda, Fiore Andrea, Petrillo Mario, Siani Alfredo, Barbieri Antonio, Arra Claudio, Rengo Franco, Hayashi Toshio, Al-Omran Mohammed, Ignarro Louis J, Napoli Claudio CXCR4/YY1 inhibition impairs VEGF network and angiogenesis during malignancy. Proceedings of the National Academy of Sciences of the United States of America. 2010; 107(32): 14484-9.
Napoli Claudio, Ignarro Louis J Nitric oxide and pathogenic mechanisms involved in the development of vascular diseases. Archives of pharmacal research. 2009; 32(8): 1103-8.
Ignarro Louis J Preface to this special journal issue on nitric oxide chemistry and biology. Archives of pharmacal research. 2009; 32(8): 1099-101.
Crimi Ettore, Ignarro Louis J, Cacciatore Francesco, Napoli Claudio Mechanisms by which exercise training benefits patients with heart failure. Nature reviews. Cardiology. 2009; 6(4): 292-300.
Strauch Berish, Herman Charles, Dabb Richard, Ignarro Louis J, Pilla Arthur A Evidence-based use of pulsed electromagnetic field therapy in clinical plastic surgery. Aesthetic surgery journal / the American Society for Aesthetic Plastic surgery. 2009; 29(2): 135-43.
d'Emmanuele di Villa Bianca Roberta, Sorrentino Raffaella, Maffia Pasquale, Mirone Vincenzo, Imbimbo Ciro, Fusco Ferdinando, De Palma Raffaele, Ignarro Louis J, Cirino Giuseppe Hydrogen sulfide as a mediator of human corpus cavernosum smooth-muscle relaxation. Proceedings of the National Academy of Sciences of the United States of America. 2009; 106(11): 4513-8.
Griscavage, JM Fukuto, JM Komori, Y Ignarro, LJ Nitric oxide inhibits neuronal nitric oxide synthase by interacting with the heme prosthetic group. Role of tetrahydrobiopterin in modulating the inhibitory action of nitric oxide. The Journal of biological chemistry. . 1994; 269(34): 21644-9.
Rajfer, J., Aronson, W.J., Bush, P.A., Dorey, F.J. and Ignarro, L.J. Nitric oxide as a mediator of relaxation of the corpus cavernosum in response to nonadrenergic, noncholinergic neurotransmission. N. Engl. J. Med 1992; 326: 90-94.