Monocyte chemoattractant proteins mediate myocardial microvascular dysfunction in swine renovascular hypertension.
BACKGROUND
Monocyte chemoattractant proteins (MCPs) play an important role in mediating inflammatory processes. Hypertension (HTN) is associated with inflammation as well as impaired cardiac microcirculatory function and structure, but the contribution of MCPs to these alterations remained unclear. This study tested the hypothesis that MCPs regulate cardiac microvascular function and structure in experimental HTN.


RESULTS
Pigs (n=6 per group) were studied after 10 weeks of normal, renovascular HTN, or renovascular HTN+ bindarit (MCPs inhibitor, 50 mg/kg/d PO). Left ventricular (LV) function, myocardial microvascular permeability, and fractional vascular volume were assessed by fast computed tomography before and after adenosine infusion (400 microg/kg/min). Myocardial fibrosis, inflammation, and microvascular remodeling were determined ex vivo. Hypertension was not altered by bindarit, but LV hypertrophy and diastolic function were improved. In response to adenosine, myocardial microvascular permeability increased in HTN (from 0.0083+/-0.0009 to 0.0103+/-0.0011 AU, P=0.038 versus baseline) and fractional vascular volume decreased, whereas both remained unchanged in normal and HTN+bindarit pigs. HTN upregulated endothelin-1 expression, myocardial inflammation, and microvascular wall thickening, which were inhibited by bindarit.


CONCLUSIONS
MCPs partly mediate myocardial inflammation, fibrosis, vascular remodeling, and impaired vascular integrity induced by hypertension. Inhibition of MCPs could potentially be a therapeutic target in hypertensive cardiomyopathy.
Lin
Jing
J
Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN 55905, USA.
Zhu
Xiangyang
X
Chade
Alejandro R
AR
Jordan
Kyra L
KL
Lavi
Ronit
R
Daghini
Elena
E
Gibson
Matthew E
ME
Guglielmotti
Angelo
A
Lerman
Amir
A
Lerman
Lilach O
LO
D000704:Analysis of Variance; D000818:Animals; D002199:Capillary Permeability / Q000502:physiology; D002478:Cells, Cultured; D017364:Collagenases / Q000378:metabolism; D003097:Collateral Circulation / Q000502:physiology; D003326:Coronary Circulation / Q000502:physiology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006978:Hypertension, Renovascular / Q000188:drug therapy / Q000378:metabolism*; D017379:Hypertrophy, Left Ventricular / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D007150:Immunohistochemistry; D053509:Matrix Metalloproteinase 13 / Q000378:metabolism; D008833:Microcirculation / Q000187:drug effects* / Q000502:physiology; D018945:Monocyte Chemoattractant Proteins / Q000378:metabolism* / Q000494:pharmacology; D009206:Myocardium / Q000378:metabolism*; D018919:Neovascularization, Physiologic; D011336:Probability; D011897:Random Allocation; D034421:Sus scrofa; D013552:Swine; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism
D018945:Monocyte Chemoattractant Proteins; D019715:Tissue Inhibitor of Metalloproteinase-1; D017364:Collagenases; D053509:Matrix Metalloproteinase 13; C417249:collagenase 1