Identification of novel biomarkers and therapeutic target candidates for stasis-heat symptom pattern of acute intracerebral hemorrhage by quantitative plasma proteomics

doi:10.19852/j.cnki.jtcm.20220617.002

Abstract

Abstract:

OBJECTIVE: To explore the novel biomarkers and therapeutic target candidates related to the stasis-heat syndrome of acute intracerebral hemorrhage (AICH). METHODS: Applying an isobaric tagging for relative and absolute quantitation-(iTRAQ-) based quantitative proteomic approach, plasma samples from AICH patients with stasis-heat, and AICH patients with non-stasis-heat and healthy control subjects were collected and analyzed to distinguish differentially expressed proteins (DEPs) correlated to AICH with stasis-heat in this block design. The standard Western blot was applied to verify DEPs. Additionally, DEPs were analyzed via bioinformatic platforms and further approved via Ingenuity Pathway Analysis (IPA). RESULTS: A total of 26 DEPs were found among AICH with the stasis-heat, AICH with non-stasis-heat, and healthy control group. The seven DEPs compared with the non-stasis-heat group are closely related to the pathogenesis of stasis heat. These proteins showed three different protein expression patterns. The alpha-1-b glycoprotein (A1BG) and copper-protein (CP) were up-regulated in the stasis-heat group, but down-regulated in the non-stasis-heat group. Compared with the non-stasis-heat group, the expression abundance of actinin, alpha 1 (ACTN1), carbonic anhydrase I (CA1), peroxiredoxin 2 (PRDX2), and vinculin (VCL) is higher in the stasis-heat group, while the CD44 is the opposite. These differences reflect that stasis-heat syndrome has more severe inflammatory immune response, coagulation disorders and damage. Bioinformatics analysis revealed that a wide variety of cellular and metabolic processes and some signaling pathways were involved in the pathophysiology of AICH with stasis-heat. AICH with stasis-heat syndrome showed more severe inflammatory reactions, tissue damage, and coagulation disorders than non-stasis heat syndrome. CONCLUSIONS: There are differences in the protein expression patterns between the stasis-heat syndrome and non-stasis-heat syndrome. These differences reflect that stasis-heat syndrome has more severe damage. CD44, CP, ACTN1, CA1, VCL, PRDX2, and A1BG could be the potential biomarkers and therapeutic target candidates of the stasis-heat subtype. This study provides a reasonable explaination for Liangxue Tongyu decoction through anti-inflammatory and brain protection treatment.

Key words: cerebral hemorrhage, stasis-heat syndrome, biomarkers, therapeutic target, quantitative plasma proteomics

WEI Lexin, LI Weiyi, TIAN Ting, ZHANG Ning, YANG Shijing, YANG Dongqing, LI Guochun, YE Fang. Identification of novel biomarkers and therapeutic target candidates for stasis-heat symptom pattern of acute intracerebral hemorrhage by quantitative plasma proteomics[J]. Journal of Traditional Chinese Medicine, 2022, 42(4): 622-632.

Figures/Tables 7

References 47

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Block	Tissue	Disease or normal	Patient number	Age/ gender	Score of stasis-heat	District and hospital	TMT labeling reagent ID	TMT labeling code
1	1	Normal	1	66/F	0	Nanjing	1	126
1	2	AICH (stasis-heat)	2	61/F	14	Nanjing	1	127
1	4	AICH (non-stasis-heat)	3	65/F	7	Nanjing	1	129
		Reference	-	-	-	-	1	131
2	6	Normal	4	60/M	0	Nanjing	2	126
2	7	AICH (stasis-heat)	5	56/M	21	Nanjing	2	127
2	9	AICH (non-stasis-heat)	6	58/M	9	Nanjing	2	129
		Reference	-	-	-	-	2	131
3	11	Normal	7	71/M	0	Zhenjiang	3	126
3	12	AICH (stasis-heat)	8	69/M	14	Zhenjiang	3	127
3	14	AICH (non-stasis-heat)	9	66/M	9	Zhenjiang	3	129
		Reference	-	-	-	-	3	131
4	16	Normal	10	56/F	0	Zhenjiang	4	126
4	17	AICH (stasis-heat)	11	61/F	13	Zhenjiang	4	127
4	19	AICH (non-stasis-heat)	12	57/F	4	Zhenjiang	4	129
		Reference	-	-	-	-	4	131

Block	Tissue	Disease or normal	Patient number	Age/ gender	Score of stasis-heat	District and hospital	TMT labeling reagent ID	TMT labeling code
1	1	Normal	1	66/F	0	Nanjing	1	126
1	2	AICH (stasis-heat)	2	61/F	14	Nanjing	1	127
1	4	AICH (non-stasis-heat)	3	65/F	7	Nanjing	1	129
		Reference	-	-	-	-	1	131
2	6	Normal	4	60/M	0	Nanjing	2	126
2	7	AICH (stasis-heat)	5	56/M	21	Nanjing	2	127
2	9	AICH (non-stasis-heat)	6	58/M	9	Nanjing	2	129
		Reference	-	-	-	-	2	131
3	11	Normal	7	71/M	0	Zhenjiang	3	126
3	12	AICH (stasis-heat)	8	69/M	14	Zhenjiang	3	127
3	14	AICH (non-stasis-heat)	9	66/M	9	Zhenjiang	3	129
		Reference	-	-	-	-	3	131
4	16	Normal	10	56/F	0	Zhenjiang	4	126
4	17	AICH (stasis-heat)	11	61/F	13	Zhenjiang	4	127
4	19	AICH (non-stasis-heat)	12	57/F	4	Zhenjiang	4	129
		Reference	-	-	-	-	4	131

No.	UniProt accession	Symbol	Entrez gene name	Abundance in SHP		Abundance in HG	Fold change	95%CI for fold change	P value
1	V9HWD8	A1BG	Alpha-1-B glycoprotein	1.678±0.102		1.127±0.359	1.490±0.091	1.490 (1.346, 1.634)	0.034
2	A0A024R694	ACTN1	Actinin, alpha 1	1.408±0.086		0.680±0.238	2.069±0.126	2.069 (0.939, 3.200)	0.051
3	P06727	APOA4	Apolipoprotein A-IV	0.772±0.078		1.418±0.334	-1.851±0.186	-1.851 (-2.147, -1.554)	0.004
4	V9HWE3	CA1	Carbonic anhydrase I	1.015±0.413		0.667±0.292	1.002±1.586	1.002 (-1.521, 3.525)	0.016
5	V9HW21	CA2	Carbonic anhydrase II	1.366±0.138		0.901±0.071	1.516±0.153	1.516 (1.136, 1.896)	0.022
6	A0A087WXI2	FCGBP	Fc fragment of igg binding protein	1.076±0.095		0.801±0.180	1.343±0.118	1.343 (1.155, 1.531)	0.047
7	P02671	FGA	Fibrinogen alpha chain	1.151±0.144		0.694±0.114	1.658±0.208	1.658 (1.327, 1.989)	0.043
8	V9HVY1	FGB	Fibrinogen beta chain	1.069±0.042		0.719±0.145	1.487±0.058	1.487 (1.394, 1.580)	0.042
9	V9HWI6	GC	Group-specific component (vitamin D binding protein)		0.943±0.155	1.553±0.497	-1.688±0.327	-1.688 (-2.209, -1.167)	0.065
10	A8K335	GGH	Gamma-glutamyl hydrolase (conjugase, folylpolygammaglutamyl hydrolase)		1.093±0.232	0.723±0.138	1.513±0.321	1.513 (0.716, 2.310)	0.054
11	P06396	GSN	Gelsolin	0.974±0.092		1.367±0.326	-1.414±0.134	-1.414 (-1.628, -1.200)	0.049
12	D9YZU5	HBB	Hemoglobin, beta	1.201±0.741		0.511±0.205	1.782±2.468	1.782 (-2.145, 5.709)	0.056
13	Q7Z379	IGH	Immunoglobulin heavy locus	0.866±0.424		1.889±0.614	-2.504±0.998	-2.504 (-4.982, -0.026)	0.067
14	P18428	LBP	Lipopolysaccharide binding protein	1.108±0.258		0.610±0.167	1.583±0.369	1.583 (0.996, 2.170)	0.067
15	V9HWF6	ORM1	Orosomucoid 1	0.837±0.097		0.472±0.121	1.774±0.206	1.774 (1.446, 2.102)	0.031
16	P07737	PFN1	Profilin 1	1.276±0.326		0.758±0.238	1.682±0.410	1.682 (0.998, 2.366)	0.022
17	D3JV41	PPBP	Pro-platelet basic protein (chemokine (C-X-C motif) ligand 7)	1.433±0.508		0.627±0.095	2.284±0.810	2.284 (0.995, 3.574)	0.041
18	B4DF70	PRDX2	Peroxiredoxin 2	1.423±0.209		0.735±0.111	1.937±0.285	1.937 (1.230, 2.645)	0.009
19	A8K2W3	SDPR	Serum deprivation response	1.066±0.332		0.449±0.068	2.377±0.741	2.377 (0.538, 4.217)	0.053
20	A2VCK8	TMSB10/TMSB4X	Thymosin beta 10	1.762±0.221		0.634±0.262	2.778±0.349	2.778 (2.223, 3.333)	0.029
21	A0A024QZN4	VCL	Vinculin	1.369±0.125		0.852±0.141	1.607±0.146	1.607 (1.375, 1.840)	0.015

No.	UniProt accession	Symbol	Entrez gene name	Abundance in SHP		Abundance in HG	Fold change	95%CI for fold change	P value
1	V9HWD8	A1BG	Alpha-1-B glycoprotein	1.678±0.102		1.127±0.359	1.490±0.091	1.490 (1.346, 1.634)	0.034
2	A0A024R694	ACTN1	Actinin, alpha 1	1.408±0.086		0.680±0.238	2.069±0.126	2.069 (0.939, 3.200)	0.051
3	P06727	APOA4	Apolipoprotein A-IV	0.772±0.078		1.418±0.334	-1.851±0.186	-1.851 (-2.147, -1.554)	0.004
4	V9HWE3	CA1	Carbonic anhydrase I	1.015±0.413		0.667±0.292	1.002±1.586	1.002 (-1.521, 3.525)	0.016
5	V9HW21	CA2	Carbonic anhydrase II	1.366±0.138		0.901±0.071	1.516±0.153	1.516 (1.136, 1.896)	0.022
6	A0A087WXI2	FCGBP	Fc fragment of igg binding protein	1.076±0.095		0.801±0.180	1.343±0.118	1.343 (1.155, 1.531)	0.047
7	P02671	FGA	Fibrinogen alpha chain	1.151±0.144		0.694±0.114	1.658±0.208	1.658 (1.327, 1.989)	0.043
8	V9HVY1	FGB	Fibrinogen beta chain	1.069±0.042		0.719±0.145	1.487±0.058	1.487 (1.394, 1.580)	0.042
9	V9HWI6	GC	Group-specific component (vitamin D binding protein)		0.943±0.155	1.553±0.497	-1.688±0.327	-1.688 (-2.209, -1.167)	0.065
10	A8K335	GGH	Gamma-glutamyl hydrolase (conjugase, folylpolygammaglutamyl hydrolase)		1.093±0.232	0.723±0.138	1.513±0.321	1.513 (0.716, 2.310)	0.054
11	P06396	GSN	Gelsolin	0.974±0.092		1.367±0.326	-1.414±0.134	-1.414 (-1.628, -1.200)	0.049
12	D9YZU5	HBB	Hemoglobin, beta	1.201±0.741		0.511±0.205	1.782±2.468	1.782 (-2.145, 5.709)	0.056
13	Q7Z379	IGH	Immunoglobulin heavy locus	0.866±0.424		1.889±0.614	-2.504±0.998	-2.504 (-4.982, -0.026)	0.067
14	P18428	LBP	Lipopolysaccharide binding protein	1.108±0.258		0.610±0.167	1.583±0.369	1.583 (0.996, 2.170)	0.067
15	V9HWF6	ORM1	Orosomucoid 1	0.837±0.097		0.472±0.121	1.774±0.206	1.774 (1.446, 2.102)	0.031
16	P07737	PFN1	Profilin 1	1.276±0.326		0.758±0.238	1.682±0.410	1.682 (0.998, 2.366)	0.022
17	D3JV41	PPBP	Pro-platelet basic protein (chemokine (C-X-C motif) ligand 7)	1.433±0.508		0.627±0.095	2.284±0.810	2.284 (0.995, 3.574)	0.041
18	B4DF70	PRDX2	Peroxiredoxin 2	1.423±0.209		0.735±0.111	1.937±0.285	1.937 (1.230, 2.645)	0.009
19	A8K2W3	SDPR	Serum deprivation response	1.066±0.332		0.449±0.068	2.377±0.741	2.377 (0.538, 4.217)	0.053
20	A2VCK8	TMSB10/TMSB4X	Thymosin beta 10	1.762±0.221		0.634±0.262	2.778±0.349	2.778 (2.223, 3.333)	0.029
21	A0A024QZN4	VCL	Vinculin	1.369±0.125		0.852±0.141	1.607±0.146	1.607 (1.375, 1.840)	0.015

No.	UniProt accession	Symbol	Entrez gene name	Abundance in nonSHP	Abundance in HG	Fold change	95%CI for fold change	P value
1	P06727	APOA4	Apolipoprotein A-IV	0.820±0.152	1.418±0.334	–1.781±0.386	–1.77（–2.39,–1.16）	0.006
2	V9HW21	CA2	Carbonic anhydrase II	1.225±0.267	0.901±0.070	1.360±0.296	1.35（0.62,2.09）	0.073
3	H0YCV9	CD44	CD44 molecule (Indian blood group)	1.183±0.641	0.944±0.671	1.252±0.679	1.25（0.17,2.33）	0.003
4	L8EB32	COL14A1	Collagen, type XIV, alpha 1	0.994±0.138	2.573±0.453	–2.614±0.365	–2.61（–5.89,0.66）	0.087
5	Q53S54	CUL3	Cullin 3	1.406±0.472	0.496±0.144	2.831±0.950	2.82（0.46,5.19）	0.063
6	V9HWI6	GC	Group-specific component (vitamin D binding protein)	0.980±0.300	1.552±0.496	–1.679±0.422	–1.67（–2.35,–1.00）	0.083
7	P06396	GSN	Gelsolin	0.919±0.105	1.367±0.325	–1.501±0.176	–1.50（–1.78,–1.22）	0.029
8	Q6ZW64	IGH	Immunoglobulin heavy locus	1.216±0.404	0.528±0.238	2.304±0.765	2.30（1.08,3.52）	0.064
9	A0A087X0P6	IGKV2D-29	Immunoglobulin kappa variable 2D-29	0.659±0.188	1.133±0.032	–1.791±0.512	–1.79（–6.39,2.81）	0.081
10	P18428	LBP	Lipopolysaccharide binding protein	1.252±0.377	0.699±0.167	1.789±0.539	1.78（0.93,2.64）	0.018
11	V9HWF6	ORM1	Orosomucoid 1	0.985±0.323	0.471±0.120	2.090±0.686	2.08（0.99,3.18）	0.006

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