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NOVEMBER/DECEMBER 2004BERKELEY,CA -- Researchers at theU.S. Department of Energy’s LawrenceBerkeley National Laboratory havediscovered the mechanism by which anextremely rare protein mutation shieldspeople from cardiovascular disease.The discovery could lead to more potentdrug therapies that both targetcholesterol deposition and preventfuture accumulation.The mutation enables the protein to curboxidation, a harmful process in whichmolecules with unpaired electrons, alsocalled free radicals, scavenge electronsfrom healthy tissue. It’s believed to playa role in such diverse diseases asAlzheimer’s, osteoporosis, and a form ofheart disease known as atherosclerosis.In the latter disease, free radicals grabelections from lipids that line arterywalls, sparking an inflammatoryresponse that paves the way forcholesterol deposition. The mutatedprotein, however, boasts an antioxidantin the form of a sulfur-based residue thatmops up unpaired electrons andprevents them from triggering arterialinflammation, according to John K.Bielicki of Berkeley Lab’s Life SciencesDivision.Bielicki’s research solves a paradox thathas puzzled the medical world since1980, when a middle-aged Italian manwas referred to Milan’s Lipid Centerwith high blood triglyceride levels, arisk factor for heart disease. Furthertesting revealed the patient alsopossessed very low levels of highdensitylipoprotein (HDL), a goodcholesterol that exports excesscholesterol from coronary arteries. Thisprocess prevents plaque buildup thatimpedes blood flow and contributes toheart attacks.A RARE PROTEIN MUTATION OFFERSNEW HOPE FOR HEART DISEASE PATIENTSScience Contact: John, Bielicki, (510) 495-2208, jkbielicki@lbl.govMedia Contact: Dan Krotz, (510) 486-4019, dakrotz@lbl.govSubmitted by Ken FerlitaPatients with low levels of HDL aresusceptible to heart disease, yet theItalian exhibited no signs of pathology.This unlikely combination intriguedscientists, who determined that thepatient and a few dozen people from hisregion possess a mutated form ofapolipoprotein A-I protein.This important protein, known as apoA-I, both manufactures HDL particles andis responsible for their structure. In themutated form, dubbed apoA-I Milanobecause of its origin, one of the protein’samino acids is replaced with an aminoacid cysteine that has a sulfhydrylgroup. Somehow, this tiny changeenables a handful of Italians to possesslow HDL levels and remain free ofcardiovascular disease. But how?In pursuit of the answer, mostresearchers have focused on the mostcommon form of the protein. About 70percent of proteins with the Milanomutation come in pairs: one proteinattaches to another to form a dimericPAGE 28complex. The key to this pairing is adisulfide bridge in which the sulfhydrylgroup from one protein links with thesulfhydryl from another. This pairingrestricts HDL size and growth and hasbeen attributed to the HDL deficiencyobserved in people who have themutation.But 30 percent of proteins with theMilano mutation don’t form dimericcomplexes. They remain unattached asmonomeric complexes. In this soloconfiguration, the sulfhydryl isn’toccupied in a disulfide bond. It’s free,which enables it to partake in otherreactions, says Bielicki. And one ofthese reactions is quenching ions withunpaired electrons. In other words, thefree sulfhydryl form of the Milanomutation is a powerful antioxidant, andBielicki had a hunch it played a role inthe mutation’s ability to fightcardiovascular disease.In a laboratory setting, he compared themutated protein with the normal apoA-Iprotein, and determined that only themonomeric form of the mutationprotects lipids from oxidation. Thisconfirmed Bielicki’s hypothesis. Inmost people, free radicals can gounchecked as they grab electrons fromlipids that line arterial walls. But for theless than 50 people lucky enough topossess the Milano mutation, themonomeric form, with its freesulfhydryl, mops up free radicals’unpaired electrons. This satisfies freeradicals’ need to scavenge electrons813-884-2382 from arterial lipids an prevents a seriesof reactions that lead to cholesterol(ONE BLOCK NORTH OF HILLSBOROUGH AVE.) deposition.A handful of villagers from this Italian town,Limone sul Garda, possess an extremelyrare protein mutation that protects themfrom atherosclerosis.“We identified a new activity associatedwith the Milano protein that suggestsContinued on page 29.