Abstract
Tumor-suppressing subchromosomal transferable fragment cDNA 6 (TSSC6) expression is restricted to hematopoietic organs and tissues where it plays a role in hematopoietic-cell function. The ADP purinergic receptor P2Y12 is mainly expressed by platelets with important clinical significance as a target for several clinically approved antithrombotic agents. We have previously shown a physical association between P2Y12 and TSSC6 in platelets. Hence our aim was to investigate whether this physical association is translated to functional effects. To investigate this possibility, we used wild-type or TSSC6 knockout (KO) mice treated with either PBS or 50 mg/kg clopidogrel. TSSC6 KO mice treated with clopidogrel exhibited synergy in delayed kinetics of clot retraction, reduced collagen-mediated platelet aggregation, and platelet spreading on fibrinogen. Platelets derived from TSSC6 mice with P2Y12 blockade form smaller thrombi when perfused over a collagen matrix under arterial flow. Clopidogrel treated TSSC6 KO arterioles showed smaller and less stable thrombi with increased tendency to embolise in vivo. These studies demonstrate a complementary role between TSSC6 and P2Y12 receptor in platelets in regulating ‘outside in’ integrin αIIbβ3 signalling thrombus growth and stability.
| Original language | English |
|---|---|
| Pages (from-to) | 12-21 |
| Number of pages | 10 |
| Journal | Thrombosis Research |
| Volume | 161 |
| DOIs | |
| Publication status | Published - 1 Jan 2018 |
Keywords
- Clopidogrel
- Mice
- Platelets
- Purinergic P2Y
- TSSC6
Cite this
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A complementary role for tetraspanin superfamily member TSSC6 and ADP purinergic P2Y12 receptor in platelets. / Makkawi, Mohammed; Howells, David; Wright, Mark D.; Jackson, Denise E.
In: Thrombosis Research, Vol. 161, 01.01.2018, p. 12-21.Research output: Contribution to journal › Article › Research › peer-review
TY - JOUR
T1 - A complementary role for tetraspanin superfamily member TSSC6 and ADP purinergic P2Y12 receptor in platelets
AU - Makkawi, Mohammed
AU - Howells, David
AU - Wright, Mark D.
AU - Jackson, Denise E.
PY - 2018/1/1
Y1 - 2018/1/1
N2 - Tumor-suppressing subchromosomal transferable fragment cDNA 6 (TSSC6) expression is restricted to hematopoietic organs and tissues where it plays a role in hematopoietic-cell function. The ADP purinergic receptor P2Y12 is mainly expressed by platelets with important clinical significance as a target for several clinically approved antithrombotic agents. We have previously shown a physical association between P2Y12 and TSSC6 in platelets. Hence our aim was to investigate whether this physical association is translated to functional effects. To investigate this possibility, we used wild-type or TSSC6 knockout (KO) mice treated with either PBS or 50 mg/kg clopidogrel. TSSC6 KO mice treated with clopidogrel exhibited synergy in delayed kinetics of clot retraction, reduced collagen-mediated platelet aggregation, and platelet spreading on fibrinogen. Platelets derived from TSSC6 mice with P2Y12 blockade form smaller thrombi when perfused over a collagen matrix under arterial flow. Clopidogrel treated TSSC6 KO arterioles showed smaller and less stable thrombi with increased tendency to embolise in vivo. These studies demonstrate a complementary role between TSSC6 and P2Y12 receptor in platelets in regulating ‘outside in’ integrin αIIbβ3 signalling thrombus growth and stability.
AB - Tumor-suppressing subchromosomal transferable fragment cDNA 6 (TSSC6) expression is restricted to hematopoietic organs and tissues where it plays a role in hematopoietic-cell function. The ADP purinergic receptor P2Y12 is mainly expressed by platelets with important clinical significance as a target for several clinically approved antithrombotic agents. We have previously shown a physical association between P2Y12 and TSSC6 in platelets. Hence our aim was to investigate whether this physical association is translated to functional effects. To investigate this possibility, we used wild-type or TSSC6 knockout (KO) mice treated with either PBS or 50 mg/kg clopidogrel. TSSC6 KO mice treated with clopidogrel exhibited synergy in delayed kinetics of clot retraction, reduced collagen-mediated platelet aggregation, and platelet spreading on fibrinogen. Platelets derived from TSSC6 mice with P2Y12 blockade form smaller thrombi when perfused over a collagen matrix under arterial flow. Clopidogrel treated TSSC6 KO arterioles showed smaller and less stable thrombi with increased tendency to embolise in vivo. These studies demonstrate a complementary role between TSSC6 and P2Y12 receptor in platelets in regulating ‘outside in’ integrin αIIbβ3 signalling thrombus growth and stability.
KW - Clopidogrel
KW - Mice
KW - Platelets
KW - Purinergic P2Y
KW - TSSC6
UR - http://www.scopus.com/inward/record.url?scp=85034622198&partnerID=8YFLogxK
U2 - 10.1016/j.thromres.2017.11.009
DO - 10.1016/j.thromres.2017.11.009
M3 - Article
VL - 161
SP - 12
EP - 21
JO - Thrombosis Research
JF - Thrombosis Research
SN - 0049-3848
ER -