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Human microvascular dysfunction and apoptotic injury induced by AL amyloidosis light chain proteins. Am J Physiol Heart Circ Physiol 2011 Dec;301(6):H2305-12 PMID: 21963839 PMCID: PMC3233808

Pubmed ID

21963839

DOI

10.1152/ajpheart.00503.2011

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.

Author List

Migrino RQ, Truran S, Gutterman DD, Franco DA, Bright M, Schlundt B, Timmons M, Motta A, Phillips SA, Hari P

Authors

David D. Gutterman MD Sr Assoc Director, Professor in the Medicine department at Medical College of Wisconsin
Parameswaran Hari MD Chief, Professor in the Medicine department at Medical College of Wisconsin




Scopus

2-s2.0-82855181178   40 Citations

MESH terms used to index this publication - Major topics in bold

Adipose Tissue
Aged
Amyloidosis
Antioxidants
Apoptosis
Arterioles
Case-Control Studies
Cells, Cultured
Coronary Vessels
Dose-Response Relationship, Drug
Endothelial Cells
Female
Humans
Immunoglobulin Light Chains
Male
Middle Aged
Nitric Oxide
Oxidative Stress
Peroxynitrous Acid
Superoxides
Time Factors
Vasodilation
Vasodilator Agents
jenkins-FCD Prod-321 98992d628744e349846c2f62ac68f241d7e1ea70