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Articles by M. K Halushka
Total Records ( 2 ) for M. K Halushka
  L Santhanam , E. C Tuday , A. K Webb , P Dowzicky , J. H Kim , Y. J Oh , G Sikka , M Kuo , M. K Halushka , A. M Macgregor , J Dunn , S Gutbrod , D Yin , A Shoukas , D Nyhan , N. A Flavahan , A. M Belkin and D. E. Berkowitz
 

Rationale: Although an age-related decrease in NO bioavailability contributes to vascular stiffness, the underlying molecular mechanisms remain incompletely understood. We hypothesize that NO constrains the activity of the matrix crosslinking enzyme tissue transglutaminase (TG2) via S-nitrosylation in young vessels, a process that is reversed in aging.

Objective: We sought to determine whether endothelium-dependent NO regulates TG2 activity by S-nitrosylation and whether this contributes to age-related vascular stiffness.

Methods and Results: We first demonstrate that NO suppresses activity and increases S-nitrosylation of TG2 in cellular models. Next, we show that nitric oxide synthase (NOS) inhibition leads to increased surface and extracellular matrix–associated TG2. We then demonstrate that endothelium-derived bioactive NO primarily mediates its effects through TG2, using TG2–/– mice chronically treated with the NOS inhibitor l-NG-nitroarginine methyl ester (L-NAME). We confirm that TG2 activity is modulated by endothelium-derived bioactive NO in young rat aorta. In aging rat aorta, although TG2 expression remains unaltered, its activity increases and S-nitrosylation decreases. Furthermore, TG2 inhibition decreases vascular stiffness in aging rats. Finally, TG2 activity and matrix crosslinks are augmented with age in human aorta, whereas abundance remains unchanged.

Conclusions: Decreased S-nitrosylation of TG2 and increased TG activity lead to enhanced matrix crosslinking and contribute to vascular stiffening in aging. TG2 appears to be the member of the transglutaminase family primarily contributing to this phenotype. Inhibition of TG2 could thus represent a therapeutic target for age-associated vascular stiffness and isolated systolic hypertension.

  M. K Halushka , E Selvin , J Lu , A. M Macgregor and T. C. Cornish
 

Advanced glycation endproducts (AGEs) are present in the vasculature and are associated with vascular disease. We determined levels of AGEs in eight distinct adult vascular tissues using tissue microarray (TMA) technology and associated these levels with clinical characteristics. Medium-to-large caliber blood vessels were harvested from 100 adult autopsies to create 17 TMAs. AGE levels were evaluated by IHC using a polyclonal anti-AGE antibody on over 700 unique blood vessels. Slides were digitally scanned, and quantitative analysis was performed using a color deconvolution image analysis technique. Medial AGE staining was strongly correlated between all eight blood vessels. In the media, AGE staining levels were significantly higher at older ages (p=0.009), in white subjects (p<0.001) and with longer postmortem interval (PMI; p<0.0001). These associations remained significant after simultaneous adjustment for age, race/ethnicity, PMI, and diabetes status. Diabetes was associated with elevated AGE levels but only after adjustment for confounding by clinical variables including race/ethnicity, hypertension, and kidney function. This extensive vascular study shows that AGE accumulation in the macrovasculature is a global process affecting atherosclerosis-prone and -resistant vessels. It also suggests ethnicity has a previously undescribed role in vascular tissue AGE levels. This manuscript contains online supplemental material at http://www.jhc.org. Please visit this article online to view these materials. (J Histochem Cytochem 57:559–566, 2009)

 
 
 
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