This publication is protected and can be accessed only from certain IPs.
This publication is protected and can be accessed only from certain IPs.

Title: Novel mechanisms of peripheral vascular endothelial dysfunction in heart failure in Tgαq*44 mice


Red blood cells (RBC) alterations and excessive activation of angiotensin (Ang)-(1– 12)/II pathway contribute to cardiovascular pathology, but their involvement in the development of peripheral endothelial dysfunction in heart failure (HF) remains unknown. Therefore, the aim of this PhD thesis was the following: 1) To describe the relationship between the development of peripheral endothelial dysfunction and RBCs alterations in HF 2) To define the effect of exogenous Ang-(1–12) and its conversion to Ang II on endothelial function in HF, focusing particularly on chymase and vascular-derived thromboxane A2 (TXA2) involvement. In this study, a unique mouse model of chronic heart failure (HF) driven by cardiomyocyte-specific overexpression of activated Gαq protein was used (Tgαq*44 mice). In 8-month-old Tgαq*44 mice, systemic endothelial dysfunction was detected as evidenced by a decreased acetylcholine-induced vasodilation in the aorta in vivo, which was associated with impaired nitric oxide (NO) production, increased superoxide anion (O2- ) and increased eicosanoid production. Moreover, 8-month-old Tgαq*44 mice showed significant structural RBC alterations, as well as increased RBC stiffness. Erythropathy in 12-month-old Tgαq*44 mice involved significantly altered RBC shape and increased elasticity, increased red cell distribution width (RDW), poor ; RBC deformability and elevated oxidative stress (gluthatione (GSH)/glutathione disulfide (GSSG) ratio). Inhibition of arginase reversed endothelial dysfunction induced by RBCs isolated from Tgαq*44 mice, ex vivo model of RBCsendothelial interaction in the isolated aorta. Ang-(1–12) induced endothelial dysfunction in 4- and 12- month-old Tgαq*44 mice, was associated with increased Ang II generation, which was not inhibited by chymostatin, a chymase inhibitor. Moreover, TXA2 generation was upregulated in response to Ang-(1-12) or Ang II in aortic rings isolated from 12-month-old Tgαq*44 mice, but not from 4-month-old Tgαq*44 mice. Furthermore, the adverse effects of Ang-(1–12) and Ang II on endotheliumdependent vasodilation in the aorta were inhibited by TXA2 receptor antagonist (SQ 29548) or Ang receptor type I antagonist (losartan) in 12-month-old-Tgαq*44 mice, but these antagonists remained without effects in 4-month-old- Tgαq*44 mice. Altogether in this Ph.D. thesis it was demonstrated that in the Tgαq*44 murine model of HF, erythropathy involving structural and biochemical alterations, upregulated arginase as well as overactivity of intravascular Ang-(1–12)/Ang II/TXA2 pathway may contribute to the development endothelial dysfunction in the aorta. Accordingly, RBC arginase and intravascular Ang-(1–12)/Ang II/TXA2 pathways may represent a novel the ; rapeutic target for systemic endothelial dysfunction in HF.

Place of publishing:


Level of degree:

2 - studia doktoranckie

Degree grantor:

Rada Dyscypliny Nauki medyczne


Chłopicki, Stefan ; Sternak, Magdalena

Date issued:




Call number:




Access rights:

tylko w bibliotece

Object collections:

Last modified:

Jun 5, 2024

In our library since:

Apr 25, 2024

Number of object content hits:


Number of object content views in PDF format


All available object's versions:


Show description in RDF format:


Show description in OAI-PMH format:


Edition name Date
ZB-140237 Jun 5, 2024


Citation style:

This page uses 'cookies'. More information