Temporal relationship between systemic endothelial dysfunction and alterations in erythrocyte function in a murine model of chronic heart failure

被引：26

作者：

Mohaissen, Tasnim ^{[1
,2
]}

Proniewski, Bartosz ^{[1
]}

Targosz-Korecka, Marta ^{[3
]}

Bar, Anna ^{[1
]}

Kij, Agnieszka ^{[1
]}

Bulat, Katarzyna ^{[1
]}

Wajda, Aleksandra ^{[1
,4
]}

Blat, Aneta ^{[1
,4
]}

Matyjaszczyk-Gwarda, Karolina ^{[1
,2
]}

Grosicki, Marek ^{[1
]}

Tworzydlo, Anna ^{[1
]}

Sternak, Magdalena ^{[1
]}

Wojnar-Lason, Kamila ^{[1
,5
]}

Rodrigues-Diez, Raquel ^{[6
,7
]}

Kubisiak, Agata ^{[3
]}

Briones, Ana ^{[6
,7
]}

Marzec, Katarzyna M. ^{[1
]}

Chlopicki, Stefan ^{[1
,5
]}

机构：

[1] Jagiellonian Univ, Jagiellonian Ctr Expt Therapeut JCET, 14 Bobrzynskiego St, PL-30348 Krakow, Poland

[2] Jagiellonian Univ, Med Coll, Fac Pharm, 9 Medyczna St, PL-30688 Krakow, Poland

[3] Jagiellonian Univ, Med Coll, Fac Phys, Inst Astron & Appl Comp Sci, 11 Lojasiewicza St, PL-30348 Krakow, Poland

[4] Jagiellonian Univ, Fac Chem, 2 Gronostajowa St, PL-30387 Krakow, Poland

[5] Jagiellonian Univ, Med Coll, Fac Med, Chair Pharmacol, 16 Grzegorzecka St, PL-31531 Krakow, Poland

[6] Univ Autonoma Madrid, Inst Invest Hosp Univ La Paz IdiPaz, Dept Farmacol, Fac Med, C Arzobispo Morcillo 4, Madrid 28029, Spain

[7] Ctr Invest Biomed Red Enfermedades Cardiovasc CIB, C Arzobispo Morcillo 4, Madrid 28029, Spain

来源：

CARDIOVASCULAR RESEARCH | 2022年 / 118卷 / 12期

关键词：

Heart failure; Endothelial dysfunction; Red blood cells; Erythropathy; NITRIC-OXIDE SYNTHASE; RED-BLOOD-CELLS; DEPENDENT VASODILATATION; DILATED CARDIOMYOPATHY; VASCULAR ENDOTHELIUM; DISTRIBUTION WIDTH; MOUSE MODEL; IN-VIVO; INHIBITION; HOSPITALIZATION;

D O I：

10.1093/cvr/cvab306

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Aims Endothelial dysfunction (ED) and red blood cell distribution width (RDW) are both prognostic factors in heart failure (HF), but the relationship between them is not clear. In this study, we used a unique mouse model of chronic HF driven by cardiomyocyte-specific overexpression of activated G alpha q protein (Tg alpha q*44 mice) to characterize the relationship between the development of peripheral ED and the occurrence of structural nanomechanical and biochemical changes in red blood cells (RBCs). Methods and results Systemic ED was detected in vivo in 8-month-old Tg alpha q*44 mice, as evidenced by impaired acetylcholine-induced vasodilation in the aorta and increased endothelial permeability in the brachiocephalic artery. ED in the aorta was associated with impaired nitric oxide (NO) production in the aorta and diminished systemic NO bioavailability. ED in the aorta was also characterized by increased superoxide and eicosanoid production. In 4- to 6-month-old Tg alpha q*44 mice, RBC size and membrane composition displayed alterations that did not result in significant changes in their nanomechanical and functional properties. However, 8-month-old Tg alpha q*44 mice presented greatly accentuated structural and size changes and increased RBC stiffness. In 12-month-old Tg alpha q*44 mice, the erythropathy was featured by severely altered RBC shape and elasticity, increased RDW, impaired RBC deformability, and increased oxidative stress (gluthatione (GSH)/glutathione disulfide (GSSG) ratio). Moreover, RBCs taken from 12-month-old Tg alpha q*44 mice, but not from 12-month-old FVB mice, coincubated with aortic rings from FVB mice, induced impaired endothelium-dependent vasodilation and this effect was partially reversed by an arginase inhibitor [2(S)-amino-6-boronohexanoic acid]. Conclusion In the Tg alpha q*44 murine model of HF, systemic ED accelerates erythropathy and, conversely, erythropathy may contribute to ED. These results suggest that erythropathy may be regarded as a marker and a mediator of systemic ED in HF. RBC arginase and possibly other RBC-mediated mechanisms may represent novel therapeutic targets for systemic ED in HF.

引用

页码：2610 / 2624

页数：15

共 60 条

[11] Addition of spironolactone to angiotensin-converting enzyme inhibition in heart failure improves endothelial vasomotor dysfunction - Role of vascular superoxide anion formation and endothelial nitric oxide synthase expression [J].