NLRP3 (Nucleotide Oligomerization Domain-Like Receptor Family, Pyrin Domain Containing 3)-Caspase-1 Inflammasome Degrades Contractile Proteins: Implications for Aortic Biomechanical Dysfunction and Aneurysm and Dissection Formation.
Increasing evidence suggests that contractile dysfunction in smooth muscle cells (SMCs) plays a critical role in aortic biomechanical dysfunction and aortic aneurysm and dissection (AAD) development. However, the mechanisms underlying SMC contractile dysfunction in sporadic AAD are poorly understood. In this study, we examined the role of the NLRP3 (nucleotide oligomerization domain-like receptor family, pyrin domain containing 3)-caspase-1 inflammasome, a key inflammatory cascade, in SMC contractile dysfunction in AAD.



We observed significant SMC contractile protein degradation in aortas from patients with sporadic thoracic AAD. The contractile protein degradation was associated with activation of the NLRP3-caspase-1 inflammasome cascade. In SMCs, caspase-1 bound and directly cleaved and degraded contractile proteins, leading to contractile dysfunction. Furthermore,Nlrp3orcaspase-1deficiency in mice significantly reduced angiotensin II-induced contractile protein degradation, biomechanical dysfunction, and AAD formation in both thoracic and abdominal aortas. Finally, blocking this cascade with the inflammasome inhibitor, glyburide (an antidiabetic medication), reduced angiotensin II-induced AAD formation.



Inflammasome-caspase-1-mediated degradation of SMC contractile proteins may contribute to aortic biomechanical dysfunction and AAD development. This cascade may be a therapeutic target in AAD formation. In addition, glyburide may have protective effects against AAD development.
From the Division of Cardiothoracic Surgery, Michael E. DeBakey Department of Surgery (D.W., P. R., Y.Z., L.Z., G.X., W.X., J.S.C., Q.Z., Y.H.S., S.A.L.), Cardiovascular Research Institute (J.S.C., Y.H.S., S.A.L.), and Department of Molecular Physiology and Biophysics (D.W., E.E.L., S.A.L.), Baylor College of Medicine, Houston, TX; Department of Cardiovascular Surgery, Texas Heart Institute, Houston (D.W., P.R., G.X., L.Z., W.X., J.S.C., Y.H.S., S.A.L.); Cardiology MD Anderson Cancer Center, Houston, Texas (S.Z.); Division of Vascular Surgery, Vanderbilt University School of Medicine, Nashville, TN (J.A.C.); and Division of Medical Genetics, Department of Internal Medicine, The University of Texas Health Science Center at Houston (D.M.M).
Darrell
D
Wu
From the Division of Cardiothoracic Surgery, Michael E. DeBakey Department of Surgery (D.W., P. R., Y.Z., L.Z., G.X., W.X., J.S.C., Q.Z., Y.H.S., S.A.L.), Cardiovascular Research Institute (J.S.C., Y.H.S., S.A.L.), and Department of Molecular Physiology and Biophysics (D.W., E.E.L., S.A.L.), Baylor College of Medicine, Houston, TX; Department of Cardiovascular Surgery, Texas Heart Institute, Houston (D.W., P.R., G.X., L.Z., W.X., J.S.C., Y.H.S., S.A.L.); Cardiology MD Anderson Cancer Center, Houston, Texas (S.Z.); Division of Vascular Surgery, Vanderbilt University School of Medicine, Nashville, TN (J.A.C.); and Division of Medical Genetics, Department of Internal Medicine, The University of Texas Health Science Center at Houston (D.M.M).
Pingping
P
Ren
From the Division of Cardiothoracic Surgery, Michael E. DeBakey Department of Surgery (D.W., P. R., Y.Z., L.Z., G.X., W.X., J.S.C., Q.Z., Y.H.S., S.A.L.), Cardiovascular Research Institute (J.S.C., Y.H.S., S.A.L.), and Department of Molecular Physiology and Biophysics (D.W., E.E.L., S.A.L.), Baylor College of Medicine, Houston, TX; Department of Cardiovascular Surgery, Texas Heart Institute, Houston (D.W., P.R., G.X., L.Z., W.X., J.S.C., Y.H.S., S.A.L.); Cardiology MD Anderson Cancer Center, Houston, Texas (S.Z.); Division of Vascular Surgery, Vanderbilt University School of Medicine, Nashville, TN (J.A.C.); and Division of Medical Genetics, Department of Internal Medicine, The University of Texas Health Science Center at Houston (D.M.M).
Yanqiu
Y
Zheng
From the Division of Cardiothoracic Surgery, Michael E. DeBakey Department of Surgery (D.W., P. R., Y.Z., L.Z., G.X., W.X., J.S.C., Q.Z., Y.H.S., S.A.L.), Cardiovascular Research Institute (J.S.C., Y.H.S., S.A.L.), and Department of Molecular Physiology and Biophysics (D.W., E.E.L., S.A.L.), Baylor College of Medicine, Houston, TX; Department of Cardiovascular Surgery, Texas Heart Institute, Houston (D.W., P.R., G.X., L.Z., W.X., J.S.C., Y.H.S., S.A.L.); Cardiology MD Anderson Cancer Center, Houston, Texas (S.Z.); Division of Vascular Surgery, Vanderbilt University School of Medicine, Nashville, TN (J.A.C.); and Division of Medical Genetics, Department of Internal Medicine, The University of Texas Health Science Center at Houston (D.M.M).
Lin
L
Zhang
From the Division of Cardiothoracic Surgery, Michael E. DeBakey Department of Surgery (D.W., P. R., Y.Z., L.Z., G.X., W.X., J.S.C., Q.Z., Y.H.S., S.A.L.), Cardiovascular Research Institute (J.S.C., Y.H.S., S.A.L.), and Department of Molecular Physiology and Biophysics (D.W., E.E.L., S.A.L.), Baylor College of Medicine, Houston, TX; Department of Cardiovascular Surgery, Texas Heart Institute, Houston (D.W., P.R., G.X., L.Z., W.X., J.S.C., Y.H.S., S.A.L.); Cardiology MD Anderson Cancer Center, Houston, Texas (S.Z.); Division of Vascular Surgery, Vanderbilt University School of Medicine, Nashville, TN (J.A.C.); and Division of Medical Genetics, Department of Internal Medicine, The University of Texas Health Science Center at Houston (D.M.M).
Gaiping
G
Xu
From the Division of Cardiothoracic Surgery, Michael E. DeBakey Department of Surgery (D.W., P. R., Y.Z., L.Z., G.X., W.X., J.S.C., Q.Z., Y.H.S., S.A.L.), Cardiovascular Research Institute (J.S.C., Y.H.S., S.A.L.), and Department of Molecular Physiology and Biophysics (D.W., E.E.L., S.A.L.), Baylor College of Medicine, Houston, TX; Department of Cardiovascular Surgery, Texas Heart Institute, Houston (D.W., P.R., G.X., L.Z., W.X., J.S.C., Y.H.S., S.A.L.); Cardiology MD Anderson Cancer Center, Houston, Texas (S.Z.); Division of Vascular Surgery, Vanderbilt University School of Medicine, Nashville, TN (J.A.C.); and Division of Medical Genetics, Department of Internal Medicine, The University of Texas Health Science Center at Houston (D.M.M).
Wanmu
W
Xie
From the Division of Cardiothoracic Surgery, Michael E. DeBakey Department of Surgery (D.W., P. R., Y.Z., L.Z., G.X., W.X., J.S.C., Q.Z., Y.H.S., S.A.L.), Cardiovascular Research Institute (J.S.C., Y.H.S., S.A.L.), and Department of Molecular Physiology and Biophysics (D.W., E.E.L., S.A.L.), Baylor College of Medicine, Houston, TX; Department of Cardiovascular Surgery, Texas Heart Institute, Houston (D.W., P.R., G.X., L.Z., W.X., J.S.C., Y.H.S., S.A.L.); Cardiology MD Anderson Cancer Center, Houston, Texas (S.Z.); Division of Vascular Surgery, Vanderbilt University School of Medicine, Nashville, TN (J.A.C.); and Division of Medical Genetics, Department of Internal Medicine, The University of Texas Health Science Center at Houston (D.M.M).
Eric E
EE
Lloyd
From the Division of Cardiothoracic Surgery, Michael E. DeBakey Department of Surgery (D.W., P. R., Y.Z., L.Z., G.X., W.X., J.S.C., Q.Z., Y.H.S., S.A.L.), Cardiovascular Research Institute (J.S.C., Y.H.S., S.A.L.), and Department of Molecular Physiology and Biophysics (D.W., E.E.L., S.A.L.), Baylor College of Medicine, Houston, TX; Department of Cardiovascular Surgery, Texas Heart Institute, Houston (D.W., P.R., G.X., L.Z., W.X., J.S.C., Y.H.S., S.A.L.); Cardiology MD Anderson Cancer Center, Houston, Texas (S.Z.); Division of Vascular Surgery, Vanderbilt University School of Medicine, Nashville, TN (J.A.C.); and Division of Medical Genetics, Department of Internal Medicine, The University of Texas Health Science Center at Houston (D.M.M).
Sui
S
Zhang
From the Division of Cardiothoracic Surgery, Michael E. DeBakey Department of Surgery (D.W., P. R., Y.Z., L.Z., G.X., W.X., J.S.C., Q.Z., Y.H.S., S.A.L.), Cardiovascular Research Institute (J.S.C., Y.H.S., S.A.L.), and Department of Molecular Physiology and Biophysics (D.W., E.E.L., S.A.L.), Baylor College of Medicine, Houston, TX; Department of Cardiovascular Surgery, Texas Heart Institute, Houston (D.W., P.R., G.X., L.Z., W.X., J.S.C., Y.H.S., S.A.L.); Cardiology MD Anderson Cancer Center, Houston, Texas (S.Z.); Division of Vascular Surgery, Vanderbilt University School of Medicine, Nashville, TN (J.A.C.); and Division of Medical Genetics, Department of Internal Medicine, The University of Texas Health Science Center at Houston (D.M.M).
Qianzi
Q
Zhang
From the Division of Cardiothoracic Surgery, Michael E. DeBakey Department of Surgery (D.W., P. R., Y.Z., L.Z., G.X., W.X., J.S.C., Q.Z., Y.H.S., S.A.L.), Cardiovascular Research Institute (J.S.C., Y.H.S., S.A.L.), and Department of Molecular Physiology and Biophysics (D.W., E.E.L., S.A.L.), Baylor College of Medicine, Houston, TX; Department of Cardiovascular Surgery, Texas Heart Institute, Houston (D.W., P.R., G.X., L.Z., W.X., J.S.C., Y.H.S., S.A.L.); Cardiology MD Anderson Cancer Center, Houston, Texas (S.Z.); Division of Vascular Surgery, Vanderbilt University School of Medicine, Nashville, TN (J.A.C.); and Division of Medical Genetics, Department of Internal Medicine, The University of Texas Health Science Center at Houston (D.M.M).
John A
JA
Curci
From the Division of Cardiothoracic Surgery, Michael E. DeBakey Department of Surgery (D.W., P. R., Y.Z., L.Z., G.X., W.X., J.S.C., Q.Z., Y.H.S., S.A.L.), Cardiovascular Research Institute (J.S.C., Y.H.S., S.A.L.), and Department of Molecular Physiology and Biophysics (D.W., E.E.L., S.A.L.), Baylor College of Medicine, Houston, TX; Department of Cardiovascular Surgery, Texas Heart Institute, Houston (D.W., P.R., G.X., L.Z., W.X., J.S.C., Y.H.S., S.A.L.); Cardiology MD Anderson Cancer Center, Houston, Texas (S.Z.); Division of Vascular Surgery, Vanderbilt University School of Medicine, Nashville, TN (J.A.C.); and Division of Medical Genetics, Department of Internal Medicine, The University of Texas Health Science Center at Houston (D.M.M).
Joseph S
JS
Coselli
From the Division of Cardiothoracic Surgery, Michael E. DeBakey Department of Surgery (D.W., P. R., Y.Z., L.Z., G.X., W.X., J.S.C., Q.Z., Y.H.S., S.A.L.), Cardiovascular Research Institute (J.S.C., Y.H.S., S.A.L.), and Department of Molecular Physiology and Biophysics (D.W., E.E.L., S.A.L.), Baylor College of Medicine, Houston, TX; Department of Cardiovascular Surgery, Texas Heart Institute, Houston (D.W., P.R., G.X., L.Z., W.X., J.S.C., Y.H.S., S.A.L.); Cardiology MD Anderson Cancer Center, Houston, Texas (S.Z.); Division of Vascular Surgery, Vanderbilt University School of Medicine, Nashville, TN (J.A.C.); and Division of Medical Genetics, Department of Internal Medicine, The University of Texas Health Science Center at Houston (D.M.M).
Dianna M
DM
Milewicz
From the Division of Cardiothoracic Surgery, Michael E. DeBakey Department of Surgery (D.W., P. R., Y.Z., L.Z., G.X., W.X., J.S.C., Q.Z., Y.H.S., S.A.L.), Cardiovascular Research Institute (J.S.C., Y.H.S., S.A.L.), and Department of Molecular Physiology and Biophysics (D.W., E.E.L., S.A.L.), Baylor College of Medicine, Houston, TX; Department of Cardiovascular Surgery, Texas Heart Institute, Houston (D.W., P.R., G.X., L.Z., W.X., J.S.C., Y.H.S., S.A.L.); Cardiology MD Anderson Cancer Center, Houston, Texas (S.Z.); Division of Vascular Surgery, Vanderbilt University School of Medicine, Nashville, TN (J.A.C.); and Division of Medical Genetics, Department of Internal Medicine, The University of Texas Health Science Center at Houston (D.M.M).
Ying H
YH
Shen
From the Division of Cardiothoracic Surgery, Michael E. DeBakey Department of Surgery (D.W., P. R., Y.Z., L.Z., G.X., W.X., J.S.C., Q.Z., Y.H.S., S.A.L.), Cardiovascular Research Institute (J.S.C., Y.H.S., S.A.L.), and Department of Molecular Physiology and Biophysics (D.W., E.E.L., S.A.L.), Baylor College of Medicine, Houston, TX; Department of Cardiovascular Surgery, Texas Heart Institute, Houston (D.W., P.R., G.X., L.Z., W.X., J.S.C., Y.H.S., S.A.L.); Cardiology MD Anderson Cancer Center, Houston, Texas (S.Z.); Division of Vascular Surgery, Vanderbilt University School of Medicine, Nashville, TN (J.A.C.); and Division of Medical Genetics, Department of Internal Medicine, The University of Texas Health Science Center at Houston (D.M.M). slemaire@bcm.edu hyshen@bcm.edu.
Scott A
SA
LeMaire
D000368:Aged; D000784:Aortic Dissection / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology / Q000517:prevention & control; D000804:Angiotensin II; D000818:Animals; D001012:Aorta, Abdominal / Q000187:drug effects / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D001013:Aorta, Thoracic / Q000187:drug effects / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D017544:Aortic Aneurysm, Abdominal / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology / Q000517:prevention & control; D017545:Aortic Aneurysm, Thoracic / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology / Q000517:prevention & control; D001696:Biomechanical Phenomena; D020170:Caspase 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005260:Female; D020022:Genetic Predisposition to Disease; D005905:Glyburide / Q000494:pharmacology; D006801:Humans; D058847:Inflammasomes / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008297:Male; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D009124:Muscle Proteins / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D059748:Proteolysis; D014661:Vasoconstriction / Q000187:drug effects
D058847:Inflammasomes; D009124:Muscle Proteins; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D000804:Angiotensin II; D020170:Caspase 1; D005905:Glyburide
aortic aneurysm; caspase 1; contractile proteins; glyburide; inflammasomes; proteolysis