title: Human microvascular dysfunction and apoptotic injury induced by AL amyloidosis light chain proteins.
abstract: Light chain amyloidosis (AL) involves overproduction of amyloidogenic light chain proteins (LC) leading to heart failure, yet the mechanisms underlying tissue toxicity remain unknown. We hypothesized that LC induces endothelial dysfunction in non-AL human microvasculature and apoptotic injury in human coronary artery endothelial cells (HCAECs). Adipose arterioles (n = 34, 50 ± 3 yr) and atrial coronary arterioles (n = 19, 68 ± 2 yr) from non-AL subjects were cannulated. Adipose arteriole dilator responses to acetylcholine/papaverine were measured at baseline and 1 h exposure to LC (20 μg/ml) from biopsy-proven AL subjects (57 ± 11 yr) without and with antioxidant cotreatment. Coronary arteriole dilation to bradykinin/papaverine was measured post-LC exposure. HCAECs were exposed to 1 or 24 h of LC. LC reduced dilation to acetylcholine (10(-4) M: 41.6 ± 7 vs. 85.8 ± 2.2% control, P < 0.001) and papaverine (81.4 ± 4.6 vs. 94.8 ± 1.3% control, P < 0.01) in adipose arterioles and to bradykinin (10(-6) M: 68.6 ± 6.2 vs. 90.9 ± 1.6% control, P < 0.001) but not papaverine in coronary arterioles. There was an increase in superoxide and peroxynitrite in arterioles treated with LC. Adipose arteriole dilation was restored by cotreatment with polyethylene glycol-superoxide dismutase and tetrahydrobiopterin but only partially restored by mitoquinone (mitochondria-targeted antioxidant) and gp91ds-tat (NADPH oxidase inhibitor). HCAECs exposed to LC showed reduced NO and increased superoxide, peroxynitrite, annexin-V, and propidium iodide compared with control. Brief exposure to physiological amounts of LC induced endothelial dysfunction in human adipose and coronary arterioles and increased apoptotic injury in coronary artery endothelial cells likely as a result of oxidative stress, reduced NO bioavailability, and peroxynitrite production. Microvascular dysfunction and injury is a novel mechanism underlying AL pathobiology and is a potential target for therapy.
authors.affiliation: Department of Cardiology and Office of Research, Phoenix Veterans Affairs Health Care System, AZ 85022, USA. raymond.migrino@va.gov
authors.forename: Raymond Q
authors.initials: RQ
authors.lastname: Migrino
authors.forename: Seth
authors.initials: S
authors.lastname: Truran
authors.forename: David D
authors.initials: DD
authors.lastname: Gutterman
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Franco
authors.forename: Megan
authors.initials: M
authors.lastname: Bright
authors.forename: Brittany
authors.initials: B
authors.lastname: Schlundt
authors.forename: Mitchell
authors.initials: M
authors.lastname: Timmons
authors.forename: Angelica
authors.initials: A
authors.lastname: Motta
authors.forename: Shane A
authors.initials: SA
authors.lastname: Phillips
authors.forename: Parameswaran
authors.initials: P
authors.lastname: Hari
mesh_terms: D000273:Adipose Tissue / Q000098:blood supply*; D000368:Aged; D000686:Amyloidosis / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis; D001160:Arterioles / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D016022:Case-Control Studies; D002478:Cells, Cultured; D003331:Coronary Vessels / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D007147:Immunoglobulin Light Chains / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009569:Nitric Oxide / Q000378:metabolism; D018384:Oxidative Stress; D030421:Peroxynitrous Acid / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D013997:Time Factors; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D000975:Antioxidants; D007147:Immunoglobulin Light Chains; D014665:Vasodilator Agents; D013481:Superoxides; D030421:Peroxynitrous Acid; D009569:Nitric Oxide