2012 NAVBO Earl P. Benditt Award - Bradford C. Berk, University of Rochester Medical Center
Dr. Berk holds the 2012 jade crystal Earl P. Benditt Award just after giving his talk, "How Many Dynes Make a Good Time?" at the NAVBO Workshops in Vascular Biology 2012 in Monterey, CA
The Earl Benditt Award was presented to Bradford C. Berk, M.D., PhD. at the NAVBO Workshop in Vascular Biology in Asilomar. This award recognized the many contributions that Dr. Berk has made to vascular biology over the duration of his career. His cleverly entitled presentation "How Many Dynes Make a Good Time" integrated his many avenues of investigation. He began his presentation with "Hemodynamics 101", summarizing many years of research by engineers, vascular biologists and physiologists, who have described the roles of shear stress, disturbed blood flow, and the predilection for atherosclerosis to occur at sites of disturbed flow. One of the most intriguing mysteries of mechano transduction is what are the shear stress receptors, and how do they transmit physical forces into biological responses.
A critical atheroprotective biomechanical pathway identified by the Berk laboratory was the MEK5-ERK5 signal transduction cascade in endothelial cells. Steady flow stimulates all of the MAP kinases with the exception of JNK. The Berk lab and many others showed activation of an atheroprotective pathway that involves MEK5- ERK5-PPARg and KLF2 signaling. Steady flow activates both anti-inflammatory and pro-survival pathways, and inhibits pro-inflammatory and death pathways such as those stimulated by TNF. Specifically, the laboratory of Dr. Wang Min and Berk showed that steady flow inhibited Apoptosis Signal Regulated Kinase (ASK1). ASK1 is activated by reactive oxygen species, as well as by TNFa, and leads to apoptosis, endothelial cell dysfunction, and inflammation. Steady flow inhibits ASK1 activation by enhanced interaction of ASK1 with its inhibitor, thioredoxin.
Because there was no change in the amount of thioredoxin, and increase in its activity Dr. Berk's laboratory hypothesized that steady flow decreased a thioredoxin inhibitory protein. This lead to the identification of thioredoxin interacting protein (TXNIP) by down regulating TXNIP under conditions of steady flow. In contrast, disturbed flow increases TXNIP expression. In TXNIP deficient mice, the up regulation of VCAM-1 by TNFa was reduced. Furthermore, endothelial TXNIP expression was increased in areas of disturbed flow (e.g. branch points) in vivo, and increased in vitro by disturbed flow. This increase in TXNIP is also required for leukocyte adhesion. KLF2 reverses TXNIP-induced leukocyte adhesion molecule expression (ICAM, VCAM) and interestingly, disturbed flow inhibits KLF2 promoter activity.
ERK5 also inhibits TNF induced JNK activation, and inhibition of this kinase by an inhibitor (BIX02188) prevents flow inhibition of TNF. Further exploration of the mechanism of ERK5 inhibition lead to the identification of a role for protein kinase C z (PKCz). PKCz is activated by disturbed flow; Berk's laboratory showed that TNF cleaved PKCz generating a catalytically active form, CAT z via activation of caspase 3; and flow inhibited this cleavage as well as caspase-3 activation, thus interrupting a positive feedback loop induced by TNF that would otherwise lead to endothelial apoptosis. PKCz crosstalk with the ERK5-KLF2 pathway thus modulates vascular inflammation. In addition to promoting leukocyte binding to endothelial cells via induction of ICAM, this kinase stimulates endothelial apoptosis via JNK and caspase 3 activation, as well as by stimulating p53 SUMOylation.
Thus flow can stimulate both atheroprotective (MEK5-ERK5-KLF2) and atheropromoting (PKCz-JNK). More recently the laboratories of Abe and Berk have shown that disturbed flow stimulates inflammation and endothelial apoptosis by promoting phosphyloration of ERK5 by PKCz, thereby inhibiting activation of KLF2. Furthermore, TXNIP inhibits KLF2 transcription by acting as a co-repressor of KLF2 gene transcription. Elucidation of the counter-regulatory pathways explains the site specific nature of atherosclerosis, with steady flow promoting anti-inflammatory, vasodilatory and pro-survival signals. In contrast, disturbed flow stimulates pro-inflammatory, vasoconstrictor and pro-death responses.
Dr. Berk acknowledged his many students, post-doctoral fellows, assistants and collaborators who contributed to the work that he presented: Jun-ichi Abe, Keigi Fujiwara, Gwen Garin, Ryan Hoefen, Zheng-Gen Jin, Geun-Young Kim, Rich Lee, Wang Min, Patrizia Nigro, Xinchun Pi, Oded Spindel, James Surapisitchat, Xiaoquin Wang, Chang-Hoon Woo, Cameron World, Hide Yamawaki and Chen Yan.
by Mary Gerritsen