THE ROLE OF ENDOTHELIAL CELL-EXPRESSED ?LPHA HEMOGLOBIN AND ITS MOLECULAR CHAPERONE AHSP IN BLOOD PRESSURE REGULATION
(Abstract release date: 05/19/16)
EHA Library. Lechauve C. 06/09/16; 134749; PB1849
Dr. Christophe Lechauve
Contributions
Contributions
Abstract
Abstract: PB1849
Type: Publication Only
Background
Because hypertention is the leading indicator of cardiovascular disease, understanding the blood pressure regulation and regional blood flow to specific vascular beds is of great medical importance. We have recently hypothesized a new mechanism for blood pressure regulation mediated specifically by the alpha subunit of hemoglobin (αHb) [1].
Aims
The α subunit (but not the β subunit of Hb) is expressed in endothelial cells (ECs) within the myoendothelial junction (MEJ), a structure in resistance arteries where ECs and smooth muscle cells (SMCs) cross-communicate to regulate vascular tone. In the MEJ, αHb is proposed to degrade NO via the dioxygenase reaction and thereby increase vascular tone. Moreover, aHb forms a complex with endothelial nitric oxide synthase (eNOS, the major local source of NO production) and cytochrome B5 reductase (CYB5R3) an enzyme that reduces ferric αHb to favor dioxygenase activity [1-3]. Alpha hemoglobin stabilizing protein (AHSP) is a molecular chaperone that binds free αHb, stabilizes its structure and also regulates its redox state, at least in the context of red blood cells [4,5]. Free αHb is extremely unstable and would not be expected to exist without a binding partner in cells. Moreover, we showed previously that AHSP converts bound ferrous αHb into a stable hexacoordinate ferric form that lacks ability to degrade NO [6,7]. Based on this data, we hypothesized that AHSP both stabilizes αHb and regulates its redox state and dioxygenase activity in vascular ECs.
Methods
We investigated this hypothesis by using vascular cell co-culture model composed of human coronary ECs and SMCs, and Ahsp-/- and alpha thalassemic mice strains.
Results
Our studies demonstrate that αHb interaction with AHSP and eNOS is mutually exclusive and αHb protein expression is disrupted in Ahsp-/- and alpha thalassemic ECs, resulting in reduced arterial tone, lowered blood pressure and abnormal arterial structure.
Conclusion
Through these mechanisms, AHSP-bound αHb may regulate blood vessel tone dynamically according to ambient conditions and CYB5R3 availability. 1. Straub AC, Lohman AW, Billaud M, Johnstone SR, Dwyer ST, et al. (2012) Endothelial cell expression of haemoglobin alpha regulates nitric oxide signalling. Nature 491: 473-477. 2. Angelo M, Hausladen A, Singel DJ, Stamler JS (2008) Interactions of NO with hemoglobin: from microbes to man. Methods Enzymol 436: 131-168.3. Gladwin MT, Lancaster JR, Jr., Freeman BA, Schechter AN (2003) Nitric oxide's reactions with hemoglobin: a view through the SNO-storm. Nat Med 9: 496-500.4. Kihm AJ, Kong Y, Hong W, Russell JE, Rouda S, et al. (2002) An abundant erythroid protein that stabilizes free alpha-haemoglobin. Nature 417: 758-763.5. Kong Y, Zhou S, Kihm AJ, Katein AM, Yu X, et al. (2004) Loss of alpha-hemoglobin-stabilizing protein impairs erythropoiesis and exacerbates beta-thalassemia. J Clin Invest 114: 1457-1466.6. Feng L, Zhou S, Gu L, Gell DA, Mackay JP, et al. (2005) Structure of oxidized alpha-haemoglobin bound to AHSP reveals a protective mechanism for haem. Nature 435: 697-701.7. Zhou S, Olson JS, Fabian M, Weiss MJ, Gow AJ (2006) Biochemical fates of alpha hemoglobin bound to alpha hemoglobin-stabilizing protein AHSP. J Biol Chem 281: 32611-326
Session topic: E-poster
Keyword(s): AHSP, Endothelial cell, Hemoglobin, Protein Expression
Type: Publication Only
Background
Because hypertention is the leading indicator of cardiovascular disease, understanding the blood pressure regulation and regional blood flow to specific vascular beds is of great medical importance. We have recently hypothesized a new mechanism for blood pressure regulation mediated specifically by the alpha subunit of hemoglobin (αHb) [1].
Aims
The α subunit (but not the β subunit of Hb) is expressed in endothelial cells (ECs) within the myoendothelial junction (MEJ), a structure in resistance arteries where ECs and smooth muscle cells (SMCs) cross-communicate to regulate vascular tone. In the MEJ, αHb is proposed to degrade NO via the dioxygenase reaction and thereby increase vascular tone. Moreover, aHb forms a complex with endothelial nitric oxide synthase (eNOS, the major local source of NO production) and cytochrome B5 reductase (CYB5R3) an enzyme that reduces ferric αHb to favor dioxygenase activity [1-3]. Alpha hemoglobin stabilizing protein (AHSP) is a molecular chaperone that binds free αHb, stabilizes its structure and also regulates its redox state, at least in the context of red blood cells [4,5]. Free αHb is extremely unstable and would not be expected to exist without a binding partner in cells. Moreover, we showed previously that AHSP converts bound ferrous αHb into a stable hexacoordinate ferric form that lacks ability to degrade NO [6,7]. Based on this data, we hypothesized that AHSP both stabilizes αHb and regulates its redox state and dioxygenase activity in vascular ECs.
Methods
We investigated this hypothesis by using vascular cell co-culture model composed of human coronary ECs and SMCs, and Ahsp-/- and alpha thalassemic mice strains.
Results
Our studies demonstrate that αHb interaction with AHSP and eNOS is mutually exclusive and αHb protein expression is disrupted in Ahsp-/- and alpha thalassemic ECs, resulting in reduced arterial tone, lowered blood pressure and abnormal arterial structure.
Conclusion
Through these mechanisms, AHSP-bound αHb may regulate blood vessel tone dynamically according to ambient conditions and CYB5R3 availability. 1. Straub AC, Lohman AW, Billaud M, Johnstone SR, Dwyer ST, et al. (2012) Endothelial cell expression of haemoglobin alpha regulates nitric oxide signalling. Nature 491: 473-477. 2. Angelo M, Hausladen A, Singel DJ, Stamler JS (2008) Interactions of NO with hemoglobin: from microbes to man. Methods Enzymol 436: 131-168.3. Gladwin MT, Lancaster JR, Jr., Freeman BA, Schechter AN (2003) Nitric oxide's reactions with hemoglobin: a view through the SNO-storm. Nat Med 9: 496-500.4. Kihm AJ, Kong Y, Hong W, Russell JE, Rouda S, et al. (2002) An abundant erythroid protein that stabilizes free alpha-haemoglobin. Nature 417: 758-763.5. Kong Y, Zhou S, Kihm AJ, Katein AM, Yu X, et al. (2004) Loss of alpha-hemoglobin-stabilizing protein impairs erythropoiesis and exacerbates beta-thalassemia. J Clin Invest 114: 1457-1466.6. Feng L, Zhou S, Gu L, Gell DA, Mackay JP, et al. (2005) Structure of oxidized alpha-haemoglobin bound to AHSP reveals a protective mechanism for haem. Nature 435: 697-701.7. Zhou S, Olson JS, Fabian M, Weiss MJ, Gow AJ (2006) Biochemical fates of alpha hemoglobin bound to alpha hemoglobin-stabilizing protein AHSP. J Biol Chem 281: 32611-326
Session topic: E-poster
Keyword(s): AHSP, Endothelial cell, Hemoglobin, Protein Expression
Abstract: PB1849
Type: Publication Only
Background
Because hypertention is the leading indicator of cardiovascular disease, understanding the blood pressure regulation and regional blood flow to specific vascular beds is of great medical importance. We have recently hypothesized a new mechanism for blood pressure regulation mediated specifically by the alpha subunit of hemoglobin (αHb) [1].
Aims
The α subunit (but not the β subunit of Hb) is expressed in endothelial cells (ECs) within the myoendothelial junction (MEJ), a structure in resistance arteries where ECs and smooth muscle cells (SMCs) cross-communicate to regulate vascular tone. In the MEJ, αHb is proposed to degrade NO via the dioxygenase reaction and thereby increase vascular tone. Moreover, aHb forms a complex with endothelial nitric oxide synthase (eNOS, the major local source of NO production) and cytochrome B5 reductase (CYB5R3) an enzyme that reduces ferric αHb to favor dioxygenase activity [1-3]. Alpha hemoglobin stabilizing protein (AHSP) is a molecular chaperone that binds free αHb, stabilizes its structure and also regulates its redox state, at least in the context of red blood cells [4,5]. Free αHb is extremely unstable and would not be expected to exist without a binding partner in cells. Moreover, we showed previously that AHSP converts bound ferrous αHb into a stable hexacoordinate ferric form that lacks ability to degrade NO [6,7]. Based on this data, we hypothesized that AHSP both stabilizes αHb and regulates its redox state and dioxygenase activity in vascular ECs.
Methods
We investigated this hypothesis by using vascular cell co-culture model composed of human coronary ECs and SMCs, and Ahsp-/- and alpha thalassemic mice strains.
Results
Our studies demonstrate that αHb interaction with AHSP and eNOS is mutually exclusive and αHb protein expression is disrupted in Ahsp-/- and alpha thalassemic ECs, resulting in reduced arterial tone, lowered blood pressure and abnormal arterial structure.
Conclusion
Through these mechanisms, AHSP-bound αHb may regulate blood vessel tone dynamically according to ambient conditions and CYB5R3 availability. 1. Straub AC, Lohman AW, Billaud M, Johnstone SR, Dwyer ST, et al. (2012) Endothelial cell expression of haemoglobin alpha regulates nitric oxide signalling. Nature 491: 473-477. 2. Angelo M, Hausladen A, Singel DJ, Stamler JS (2008) Interactions of NO with hemoglobin: from microbes to man. Methods Enzymol 436: 131-168.3. Gladwin MT, Lancaster JR, Jr., Freeman BA, Schechter AN (2003) Nitric oxide's reactions with hemoglobin: a view through the SNO-storm. Nat Med 9: 496-500.4. Kihm AJ, Kong Y, Hong W, Russell JE, Rouda S, et al. (2002) An abundant erythroid protein that stabilizes free alpha-haemoglobin. Nature 417: 758-763.5. Kong Y, Zhou S, Kihm AJ, Katein AM, Yu X, et al. (2004) Loss of alpha-hemoglobin-stabilizing protein impairs erythropoiesis and exacerbates beta-thalassemia. J Clin Invest 114: 1457-1466.6. Feng L, Zhou S, Gu L, Gell DA, Mackay JP, et al. (2005) Structure of oxidized alpha-haemoglobin bound to AHSP reveals a protective mechanism for haem. Nature 435: 697-701.7. Zhou S, Olson JS, Fabian M, Weiss MJ, Gow AJ (2006) Biochemical fates of alpha hemoglobin bound to alpha hemoglobin-stabilizing protein AHSP. J Biol Chem 281: 32611-326
Session topic: E-poster
Keyword(s): AHSP, Endothelial cell, Hemoglobin, Protein Expression
Type: Publication Only
Background
Because hypertention is the leading indicator of cardiovascular disease, understanding the blood pressure regulation and regional blood flow to specific vascular beds is of great medical importance. We have recently hypothesized a new mechanism for blood pressure regulation mediated specifically by the alpha subunit of hemoglobin (αHb) [1].
Aims
The α subunit (but not the β subunit of Hb) is expressed in endothelial cells (ECs) within the myoendothelial junction (MEJ), a structure in resistance arteries where ECs and smooth muscle cells (SMCs) cross-communicate to regulate vascular tone. In the MEJ, αHb is proposed to degrade NO via the dioxygenase reaction and thereby increase vascular tone. Moreover, aHb forms a complex with endothelial nitric oxide synthase (eNOS, the major local source of NO production) and cytochrome B5 reductase (CYB5R3) an enzyme that reduces ferric αHb to favor dioxygenase activity [1-3]. Alpha hemoglobin stabilizing protein (AHSP) is a molecular chaperone that binds free αHb, stabilizes its structure and also regulates its redox state, at least in the context of red blood cells [4,5]. Free αHb is extremely unstable and would not be expected to exist without a binding partner in cells. Moreover, we showed previously that AHSP converts bound ferrous αHb into a stable hexacoordinate ferric form that lacks ability to degrade NO [6,7]. Based on this data, we hypothesized that AHSP both stabilizes αHb and regulates its redox state and dioxygenase activity in vascular ECs.
Methods
We investigated this hypothesis by using vascular cell co-culture model composed of human coronary ECs and SMCs, and Ahsp-/- and alpha thalassemic mice strains.
Results
Our studies demonstrate that αHb interaction with AHSP and eNOS is mutually exclusive and αHb protein expression is disrupted in Ahsp-/- and alpha thalassemic ECs, resulting in reduced arterial tone, lowered blood pressure and abnormal arterial structure.
Conclusion
Through these mechanisms, AHSP-bound αHb may regulate blood vessel tone dynamically according to ambient conditions and CYB5R3 availability. 1. Straub AC, Lohman AW, Billaud M, Johnstone SR, Dwyer ST, et al. (2012) Endothelial cell expression of haemoglobin alpha regulates nitric oxide signalling. Nature 491: 473-477. 2. Angelo M, Hausladen A, Singel DJ, Stamler JS (2008) Interactions of NO with hemoglobin: from microbes to man. Methods Enzymol 436: 131-168.3. Gladwin MT, Lancaster JR, Jr., Freeman BA, Schechter AN (2003) Nitric oxide's reactions with hemoglobin: a view through the SNO-storm. Nat Med 9: 496-500.4. Kihm AJ, Kong Y, Hong W, Russell JE, Rouda S, et al. (2002) An abundant erythroid protein that stabilizes free alpha-haemoglobin. Nature 417: 758-763.5. Kong Y, Zhou S, Kihm AJ, Katein AM, Yu X, et al. (2004) Loss of alpha-hemoglobin-stabilizing protein impairs erythropoiesis and exacerbates beta-thalassemia. J Clin Invest 114: 1457-1466.6. Feng L, Zhou S, Gu L, Gell DA, Mackay JP, et al. (2005) Structure of oxidized alpha-haemoglobin bound to AHSP reveals a protective mechanism for haem. Nature 435: 697-701.7. Zhou S, Olson JS, Fabian M, Weiss MJ, Gow AJ (2006) Biochemical fates of alpha hemoglobin bound to alpha hemoglobin-stabilizing protein AHSP. J Biol Chem 281: 32611-326
Session topic: E-poster
Keyword(s): AHSP, Endothelial cell, Hemoglobin, Protein Expression
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