Ukuvuselela inqubo enciphayo njengoba sikhula kungase kuvikele ku-atherosclerosis, imbangela enkulu yokuhlaselwa yinhliziyo nokushaywa unhlangothi. Ekutholakaleni okushicilelwe ku-inthanethi namuhla ku-Proceedings of the National Academy of Sciences (PNAS), ososayensi base-Albert Einstein College of Medicine eholwa ngu-Ana Maria Cuervo, MD, Ph.D., banciphise ngempumelelo uqweqwe oluncipha umthambo kumagundane abengathuthukisa lezo izilonda. Abacwaningi bakwenze lokho ngokuthuthukisa i-chaperone-mediated autophagy (CMA), inqubo yokugcinwa kwendlu yamaselula uDkt. Cuervo ayithola ngo-1993 futhi wayiqamba ngo-2000.
“Siye sabonisa kulolu cwaningo ukuthi sidinga i-CMA ukuze ivikeleke ku-atherosclerosis, okuba nzima futhi iqhubeke lapho i-CMA incipha—into eyenzekayo nalapho abantu bekhula,” kusho uDkt. , uSihlalo kaRobert noRenée Belfer we-Study of Neurodegenerative Diseases, kanye nomqondisi-kanye we-Institute for Aging Research e-Einstein. "Kodwa okubaluleke ngokufanayo, sikhombisile ukuthi ukwanda komsebenzi we-CMA kungaba isu elisebenzayo lokunqanda isifo sokuqina kwemithambo yegazi kanye nokumisa ukuqhubeka kwayo."
I-CV ye-CMA ehlaba umxhwele
I-CMA igcina amangqamuzana esebenza ngokujwayelekile ngokonakalisa ngokukhetha amaprotheni amaningi aqukethwe amaseli. Ku-CMA, amaprotheni akhethekile "angu-chaperone" abopha amaprotheni ku-cytoplasm futhi awaqondise ezakhiweni zamaselula ezigcwele i-enzyme ebizwa ngokuthi ama-lysosomes ukuze agaywe futhi asetshenziswe kabusha. UDkt. Cuervo uye wachaza abadlali abaningi bamangqamuzana abathintekayo ku-CMA futhi wabonisa ukuthi i-CMA, ngokuwohloka kwayo ngesikhathi kwamaprotheni abalulekile, ilawula izinqubo eziningi ze-intracellular ezihlanganisa i-glucose ne-lipid metabolism, isigqi se-circadian kanye nokulungiswa kwe-DNA. Uphinde wathola ukuthi i-CMA ephazamisekile ivumela amaprotheni alimele ukuthi aqongelele emazingeni anobuthi, okunomthelela ekugugeni futhi-lapho ukunqwabelana okunobuthi kwenzeka kumangqamuzana ezinzwa-kuya ezifweni ze-neurodegenerative ezihlanganisa i-Parkinson, i-Alzheimer's, nesifo sikaHuntington.
Izimpumelelo zikaDkt. Cuervo zaqashelwa ngo-2019 ngenkathi ekhethwa ku-National Academy of Sciences (NAS). Ngo-1996, i-NAS yaqala ukumema amalungu ayo asanda kukhethwa ukuthi athumele Isihloko Esikhethekile Sokuvula ku-PNAS esasizogcizelela amagalelo esayensi elungu. Ngenxa yokubambezeleka okuhlobene nobhubhane lwe-COVID-19, iphepha lanamuhla lendima yokuvikela ye-CMA ngokumelene nesifo sokuqina kwemithambo yegazi yiphepha lokuqala likaDkt. Cuervo le-PNAS futhi lengeza emgudwini wakhe womsebenzi ngokubaluleka kwe-CMA.
Ukulwa Ne-Plaque
Isifo senhliziyo (i-CVD) siyimbangela yokufa ehamba phambili emhlabeni, ngaphezu kuka-80% walabo abafa ngenxa yesifo senhliziyo nokushaywa unhlangothi. I-CVD, yona, ivame ukuhlotshaniswa ne-atherosclerosis: ukwakheka kwe-plaque (into enamathelayo equkethe amafutha, i-cholesterol, i-calcium, nezinye izinto) ngaphakathi kwezindonga zemithambo. Ukunqwabelana koqwembe kuqina futhi kunciphise imithambo, kuyivimbele ekuletheni igazi elinomoya-mpilo emisipheni yenhliziyo (okuholela ekuhlaselweni kwenhliziyo), ubuchopho (ukushaywa unhlangothi), kanye nawo wonke umzimba.
Ukuze kuphenywe indima ye-CMA ku-atherosclerosis, uDkt. Cuervo kanye nozakwabo bakhuthaze isifo sokuqina kwemithambo yegazi kumagundane ngokuwapha ukudla okunamafutha aseNtshonalanga amasonto e-12 nokuqapha umsebenzi we-CMA kuma-aorta athintekile ezilwaneni. Umsebenzi we-CMA ekuqaleni wanda ekuphenduleni inselele yokudla; ngemva kwamasonto angu-12, nokho, ukwakheka koqweqwe lwawo kwakubalulekile, futhi cishe awukho umsebenzi we-CMA owawungatholwa ezinhlotsheni ezimbili zamangqamuzana—ama-macrophage namangqamuzana emisipha abushelelezi emithanjeni—aziwa ngokungasebenzi kahle kwe-atherosclerosis, okuholela ekwakhekeni koqweqwe olungaphakathi emithanjeni.
"I-CMA ibonakala ibaluleke kakhulu ekuvikeleni ama-macrophage namangqamuzana emisipha abushelelezi-awasiza ukuba asebenze ngokujwayelekile naphezu kokudla kwe-pro-atherosclerotic-okungenani okwesikhashana, kuze kube yilapho umsebenzi wabo we-CMA uphela ngokuyisisekelo," kusho uDkt. Cuervo. Waphawula ukuthi ukuphakela amagundane ukudla okunamafutha amaningi ashoda ngokuphelele emsebenzini we-CMA kuveza ubufakazi obunamandla nakakhulu bokubaluleka kwe-CMA: ama-plaque amakhulu acishe abe ngu-40% kunalawo ezilwane ezilawulayo ezazidla ukudla okunamafutha amaningi.
Eyamagundane Kanye Nabesilisa
Abacwaningi bathola ubufakazi bokuthi umsebenzi obuthakathaka we-CMA uhambisana ne-atherosclerosis nakubantu. Ezinye iziguli ezike zashaywa unhlangothi zenza inqubo yokuhlinzwa, eyaziwa ngokuthi i-carotid endarterectomy, esusa izingxenye ezithinteke ku-plaque emithanjeni yazo ye-carotid ukuze kuncishiswe ingozi yokushaywa unhlangothi kwesibili. UDkt. Cuervo kanye nozakwabo bahlaziye umsebenzi we-CMA ezingxenyeni ze-carotid artery kusuka kuziguli zokuqala ze-62 ezalandelwa iminyaka emithathu ngemva kokuhlinzwa kwazo.
"Lezo ziguli ezinamazinga aphezulu e-CMA kulandela ukushaywa kwazo kokuqala azizange zithole okwesibili, kuyilapho ukushaywa kwesibili kwenzeka cishe kuzo zonke iziguli ezinomsebenzi ophansi we-CMA," kusho uDkt. Cuervo. "Lokhu kusikisela ukuthi izinga lomsebenzi wakho we-CMA wangemva kwe-endarterectomy lingasiza ekubikezeleni ubungozi bokushaywa unhlangothi kwesibili nasekuqondiseni ukwelashwa, ikakhulukazi kubantu abane-CMA ephansi."
Ukuvula i-CMA, Ukulungisa I-Atherossteosis
Ucwaningo lungowokuqala ukukhombisa ukuthi ukuvula i-CMA kungaba yindlela ephumelelayo yokuvimbela isifo sokuqina kwemithambo yegazi ekubeni sibi kakhulu noma siqhubekele phambili. Abacwaningi ngokwezakhi zofuzo i-CMA "eyakhiwe" kumagundane anikezwa ukudla okune-pro-atherosclerotic, okunamafutha aphezulu aseWestern futhi kamuva awaqhathanisa namagundane okulawula adla ukudla okufanayo kwamaviki e-12. Amagundane akhuthazwe yi-CMA aye athuthuke kakhulu amaphrofayili e-lipid yegazi, ngamazinga anciphe kakhulu e-cholesterol uma kuqhathaniswa namagundane okulawula. Izilonda ze-plaque ezakheka kumagundane aguqulwe ngofuzo zazizincane kakhulu futhi zithambile ngokuqina uma kuqhathaniswa nama-plaque ekulawuleni amagundane. Ngenhlanhla, abantu ngeke badinge ukuguqulwa kofuzo ukuze bazuze kulokhu kutholwa.
"Mina nozakwethu siye sakha izinhlanganisela zezidakamizwa eziye zabonisa isithembiso sokwandisa ngokuphepha nangempumelelo umsebenzi we-CMA kumathishu amaningi egundane nasemangqamuzaneni athathwe abantu," kusho uDkt. Cuervo. U-Einstein ufake impahla yengqondo kulobu buchwepheshe obuyisisekelo.
Iphepha le-PNAS linesihloko esithi "Indima yokuvikela ye-chaperone-mediated autophagy ngokumelene ne-atherosclerosis." Abanye ababhali be-Einstein kwakunguJulio Madrigal-Matute, Ph.D., Dario F. Riascos-Bernal, Antonio Diaz, MD, Ph.D., Inmaculada Tasset, Ph.D., Adrian Martin-Segura, Ph.D., Susmita Kaushik, Ph.D., Simoni Tiano, MD, Matthieu Bourdenx, Ph.D., Gregory J. Krause, MS, Nicholas Sibinga, MD, Fernando Macian, MD, Ph.D., kanye noRajat Singh, MD Elinye iphepha umbhali ohambisana naye nguJudith C. Sluimer, Ph.D., waseMaastricht University Medical Center e-Netherlands kanye neNyuvesi yase-Edinburgh e-United Kingdom.
LOKHO ONGAKUTHATHE KULESI SIHLOKO:
- Cuervo, professor of developmental and molecular biology and of medicine, the Robert and Renée Belfer Chair for the Study of Neurodegenerative Diseases, and co-director of the Institute for Aging Research at Einstein.
- After 12 weeks, however, plaque buildup was significant, and virtually no CMA activity could be detected in the two types of cells—macrophages and arterial smooth muscle cells—that are known to malfunction in atherosclerosis, leading to the buildup of plaque within arteries.
- Cuervo and colleagues promoted atherosclerosis in mice by feeding them a fatty Western diet for 12 weeks and monitoring CMA activity in plaque-affected aortas of the animals.
