Biomedical Engineering Reference
In-Depth Information
Table 1.2
In vitro and biological substrates of DP8 and DP9.
Demonstrated
cleavage Substrate N-terminal sequence References
DP8, DP9 GLP-1
(7-36)
His-Ala k Glu-Gly-Thr-Phe- 122
GLP-2
(1-33)
His-Ala k Glu-Gly-Ser-Phe- 122
NPY
(1-36)
Tyr-Pro k Ser-Lys-Pro-Asp- 122,133
PYY
(1-36)
Tyr-Pro k Ile-Lys-Pro-Glu- 122
DP8 SDF-1a (CXCL12)
(1-68)
Lys-Pro k Val-Ser-Leu-Ser- 192
SDF-1b (CXCL12)
(1-72)
Lys-Pro k Val-Ser-Leu-Ser- 192
IP-10 (CXCL10)
(1-77)
Val-Pro k Leu-Ser-Arg-Thr- 192
I-TAC (CXCL11)
(1-73)
Phe-Pro k Met-Phe-Lys-Arg- 192
DP9 RU1
(34-42)
Val-Pro k Tyr-Gly-Ser-Phe- 202
Cleavage sites are indicated with an arrow, and DP8/9 cleaved dipeptides are indicated in bold.
where many of these substrates are found, but physiological relevance, if any,
of NPY as a potential DP8/9 substrate is yet to be revealed, especially given
that most substrates are soluble and secreted, while DP8/9 are localized in the
cytoplasm.
1.6.2 Cardiovascular Effects
In addition to the implicated roles of DP4 in cardiovascular function via NPY
truncation, a number of other substrates exerting cardiovascular effects are
described. Bradykinin is an important vasoactive peptide involved in blood-
pressure homeostasis that is primarily metabolized by ACE, but can also be
degraded by the consecutive action of aminopeptidase P and DP4. Amino-
peptidase P first removes an N-terminal arginine residue allowing DP4 to then
cleave a Pro-Pro dipeptide from the N-terminus.
160
Substance P is also a
substrate of ACE
203
along with other proteases including DP4.
204
Inhibitors of
ACE are used widely for the treatment of hypertension, congestive heart failure
and impaired renal function, but angioedema is a potentially life-threatening
adverse side effect that can result from ACE inhibitors. The angioedema side-
effect is thought to arise potentially from impaired degradation of ACE sub-
strates, bradykinin, and substance P, by DP4 and aminopeptidase P due to
decreased DP4 activity during ACE-inhibitor-associated angioedema.
205,206
Co-administration of an ACE inhibitor with a DP4 inhibitor, vildagliptin (for
treatment of type II diabetes), has been shown to increase significantly the risk
of angioedema.
207
It should be noted that administration of the DP4 inhibitor
alone did not increase the risk of angioedema,
207
thus highlighting the complex
interplay between ACE inhibition, DP4 activity, and degradation of the
vasoactive peptides, bradykinin and substance P in the development of ACE-
inhibitor-associated angioedema. In addition to these findings, DP4 cleavage of
vasostatin I, a chromogranin A-derived peptide implicated in the regulation of
cardiovascular function,
208
has been demonstrated in vitro.
165
However, to our
knowledge, no further studies involving vasostatin I as a potential DP4
