Date of Degree
PhD (Doctor of Philosophy)
Faraci, Frank M.
First Committee Member
Faraci, Frank M.
Second Committee Member
Heistad, Donald D.
Third Committee Member
Lamping, Kathryn G.
Fourth Committee Member
Fifth Committee Member
Sigmund, Curt D.
Angiotensin II (Ang II) promotes vascular disease and hypertension, in part, by activating the interleukin-6 (IL-6)/signal transducer and activator of transcription 3 (STAT3) signaling pathway. Extensive studies have demonstrated that SOCS3 plays an important role in suppressing the IL-6/STAT3 pathway in the immune system and in cancer biology. In contrast, the functional importance of SOCS3 in cardiovascular disease is largely unknown. Thus, the overall goal of these studies was to investigate the role of SOCS3 in models of Ang II-dependent vascular disease and hypertension.
To examine direct effects of Ang II on the vessel wall, carotid arteries from SOCS3 haplodeficient (SOCS3+/-) mice and wild-type littermates (SOCS3+/+) were incubated with the peptide or vehicle for 22 hrs, followed by examination of endothelial function using acetylcholine. Relaxation to acetylcholine was similar in all arteries incubated with vehicle. A low concentration of Ang II (1 nmol/L) did not affect acetylcholine-induced vasodilation in SOCS3+/+ mice, but reduced responses in arteries from SOCS3+/- mice by ~50% (P<0.05). This Ang II-induced endothelial dysfunction in SOCS3+/- mice was prevented by inhibitors of NF-êB or STAT3, an IL-6 neutralizing antibody, or a scavenger of superoxide. Responses to nitroprusside, an endothelium-independent vasodilator, were similar in all groups.
To test the importance of SOCS3 in vivo, mice were infused systemically with a pressor dose of Ang II (1.4 mg/kg per day) or vehicle for 14 days via osmotic mini-pumps. Acetylcholine-induced vasodilation in carotid and resistance arteries in brain from SOCS3+/- mice was reduced by ~60% (P<0.05). Surprisingly, genetic deficiency in SOCS3 prevented the majority of Ang II-induced endothelial dysfunction without affecting the pressor response to Ang II.
To investigate potential mechanisms underlying divergent results when studying effects of local versus systemic effects of Ang II, we performed bone marrow transplantation followed by infusion of vehicle or Ang II for two weeks. Lethally irradiated WT (CD45.1) mice reconstituted with SOCS3+/- bone marrow were protected from Ang II-induced endothelial dysfunction (P<0.05), while reconstitution of irradiated SOCS3+/- mice with WT (CD45.1) bone marrow exacerbated Ang II-induced vascular dysfunction (P<0.05). WT (CD45.1) into SOCS3+/+ and SOCS3+/- into SOCS3+/- bone marrow chimeras exhibited vascular function consistent with non-irradiated controls. In addition, the pressor response to Ang II was reduced by ~50% in WT mice reconstituted with bone marrow from SOCS3+/- mice (P<0.05).
These data suggest that SOCS3 exerts divergent or context-dependent effects depending on whether vascular dysfunction was due to local versus systemic administration of Ang II. SOCS3 deficiency in the vessel wall enhanced local detrimental effects of Ang II on vascular function. In contrast, bone marrow-derived cells that are haplodeficient in SOCS3 protect against systemically administered Ang II and the resulting vascular dysfunction and hypertension.
To my knowledge, these are the first experimental studies that begin to define the importance of SOCS3 in Ang II-induced hypertension and endothelial dysfunction. Results obtained from these experiments provide new insight into mechanisms which regulate oxidative stress and inflammation within the vasculature. The studies also revealed that bone marrow-derived cells that are haplodeficient in SOCS3 protect against pressor and endothelial effects of Ang II. These findings may eventually contribute to the development of novel therapeutic approaches for hypertension and hypertension associated end-organ damage.
Hypertension is the leading risk factor for cardiovascular disease and stroke, which ranks as the number one and number four causes of death in the United States, respectively. Although hypertension is a common health issue worldwide, the pathophysiology of its development and mechanisms that underlie subsequent end-organ damage have not been fully defined.
My thesis project was aimed at investigating whether an inhibitory protein in the immune system plays an important role in the development and progression of high blood pressure and vascular disease. The project also aimed to understand how this protein may promote or protects against this disease condition.
Results obtained from a series of studies provided evidence which strongly support the concept that this specific protein exerts functionally important effects in animal models of hypertension and vascular disease. Using a genetically engineered mouse model which lacks this specific protein, my data suggests the protein plays a divergent role in the vasculature versus the whole body. In isolated arteries, lack of this protein are harmful. Surprisingly, studies conducted in whole animals revealed that lack of this same protein had a protective role in response to the same stimuli. Lastly, I obtained evidence that bone marrow-derived cells were responsible for these protective effects.
The present study defined the role of a protein named suppressor of cytokine signaling 3 in vascular disease for the first time. The work may provide insight into new strategies to protect against vascular disease, hypertension, and subsequent clinical events.
publicabstract, Angiotensin II, Endothelial function, Hypertension, Interleukin 6, Suppressor of cytokine signaling 3
xii, 166 pages
Includes bibliographical references (pages 139-166).
Copyright 2014 Ying Li
Li, Ying. "Mechanisms of vascular disease: divergent roles for suppressor of cytokine signaling 3 in angiotensin II-induced vascular dysfunction." PhD (Doctor of Philosophy) thesis, University of Iowa, 2014.