Thesis (M.S. in food science)--Washington State University, December 2007. / Includes bibliographical references.

Na+ sensitive hypertension in Dahl salt sensitive rats (Dahl S) or spontaneously hypertensive rats (SHR) is linked to intrinsic changes in the brain that favour increased Na+ entry into the cerebrospinal fluid (CSF) followed by increases in sympathetic hyperactivity and hypertension (Huang et al 2004). Similar responses are observed in salt resistant and Wistar rats that receive an intracerebroventricular (icv) infusion of Na+ rich artificial cerebrospinal fluid (aCSF) (Huang et al 2001, 2006). Downstream to increased CSF[Na+], a pathway has been described involving mineralocorticoid receptors (MRs), benzamil sensitive Na+ channels, “ouabain”, and angiotensin II type 1 receptors (AT1-R) (Huang et al 1998, Zhao et al 2001, Wang and Leenen 2003, Huang et al 2008). Blood pressure (BP) responses to increased CSF[Na+] may involve activation of AT1-R in the subfornical organ (SFO) as the BP response to injection of NaCl into a lateral ventricle can be blocked by AT1-R blockade in the SFO (Rohmeiss et al 1995a). The role of aldosterone and AT1-R in the SFO was investigated in mediating the BP and heart rate (HR) response to increases in CSF[Na+] and local [Na+]. Results show that infusion of 0.45M and 0.6M Na+ rich aCSF into the SFO increases BP but not HR. The BP is unchanged by infusion of a mannitol solution osmotically equivalent to 0.6M Na+ rich aCSF indicating that the SFO is Na+ sensitive. The BP response to a lower concentration of Na+ (0.45M) is enhanced by prior infusion of aldosterone while BP response to 0.6M is not further enhanced suggesting that the SFO may have maximal responsiveness to acute increases in [Na+] at 0.6M. The BP responses to Na+ rich aCSF in the SFO and the enhancement of those responses by aldosterone can be blocked by infusion of the AT1-R blocker Candesartan in the SFO. This response appears therefore to be mediated in the SFO through AT1-R activation, likely through Ang II release in the SFO. ICV infusion of Na+ rich aCSF increases BP but not HR and this response is partially blocked by infusion of the AT1-R blocker Candesartan in the SFO. This indicates that nearly half the BP responses to icv infusion of Na+ rich aCSF is mediated through AT1-R activation in the SFO. Lastly, contrary to icv, PVN and MnPO studies (Huang and Leenen 1996, Budzikowski and Leenen 2001, Gabor and Leenen 2009) ouabain in the SFO does not increase BP or HR. In conclusion, these results show that the SFO is Na+ sensitive and mediates half the BP responses to changes in CSF[Na+] through a mechanism that involves AT1-R activation. The SFO is further sensitized to Na+ by aldosterone presumably through its genomic effects. Lastly, ouabain in the SFO does not increase BP or HR suggesting that endogenous ouabain in the SFO is not involved in modulating BP or HR responses.

Angiotensin II (Ang II) is an important modulator for development of atherosclerosis from early stage foam cell formation to advanced stage plaque rupture. Recently, the importance of locally generated Ang II, especially in macrophages, has become more evident. Generation of Ang II by several enzymes other than ACE and renin has been shown mainly in vitro. Cathepsin G is one these enzymes which is expressed in neutrophils and macrophages. Macrophages are one of the primary and crucial cells in atherosclerotic lesions which become lipid-laden foam cells through lipoprotein uptake. We hypothesized that activation of nuclear factors in foam cells increases Ang II by modulation of the renin angiotensin system (RAS) genes and cathepsin G. We also hypothesized that cathepsin G, through its Ang II generating activity and its other catalytic functions, promotes atherosclerosis. The present study assessed the Ang I and II levels and expression of the RAS genes in THP-1 cells, a human acute monocytic leukemia cell line, and in peritoneal and bone marrow-derived macrophages after exposure to acetylated LDL (ac-LDL). I also evaluated how RAS blockade would affect foam cell formation in THP-1 cells. In parallel, I assessed the role of cathepsin G in Ang II generation and in the progression of atherosclerosis in cathepsin G heterozygous knockout mice on an Apoe-/- background (Ctsg+/-Apoe-/- mice). Ac-LDL treatment increased Ang I and Ang II levels in cell lysates and media from THP-1 cells but not in peritoneal or bone marrow-derived macrophages from wild type C57BL/6 mice. In ac-LDL-treated THP-1 cells, ACE and cathepsin G mRNA levels and activities were elevated. Angiotensinogen mRNA is increased but not the angiotensinogen protein concentration. Renin mRNA level and activity were not altered by ac-LDL treatment. Blocking RAS by an AT1 receptor blocker, ACE inhibitors or a renin inhibitor decreased cholesteryl ester content of THP-1 cells after exposure to ac-LDL. To confirm that the Ang II effect on foam cell formation was not unique to ac-LDL, we treated the THP-1 macrophages with a renin inhibitor or an AT1 receptor inhibitor after exposure to oxidized LDL (ox-LDL). RAS blockade in ox-LDL-treated cells also abolished cholesteryl ester formation. To see how Ang II plays a role in foam cell formation we assessed the effect of RAS inhibitors on SR-A, the principal receptor for mediating ac-LDL entry into the cells and on acyl-CoA:cholesterol acyl transferase (ACAT-1), the enzyme responsible for intracellular cholesterol esterification. RAS blockade in both ac-LDL- and ox-LDL-treated cells decreased SR-A and ACAT-1 protein levels. Cathepsin G partial deficiency on an Apoe-/- background did not change Ang II levels in peritoneal or bone marrow-derived macrophage cell lysates or media. This deficiency also did not affect immunoreactive angiotensin peptide levels in atherosclerotic lesions. After 8 weeks on a high fat diet Ctsg+/-Apoe-/- mice were similar to Ctsg+/+Apoe-/- mice in terms of lesion size and serum cholesterol levels but the Ctsg+/+Apoe-/- mice had more advanced lesions with more collagen and smooth muscle cells and fewer macrophages. Moreover, Ctsg+/+Apoe-/- mice had more apoptotic cells than their Ctsg+/-Apoe-/- littermates. Overall, our findings indicate that Ang II is increased in foam cells and this endogenous Ang II is involved in cholesteryl ester formation, possibly by regulating the levels of ACAT-1 and SR-A. We did not find any role for cathepsin G in generation of Ang II in mice but cathepsin G does, nevertheless, promote the progression of atherosclerotic lesions to a more advanced stage.

Environmental factors such as ambient temperature and oxygen availability are variation in different altitude. Individuals within a species, living in variable environments often display phenotypic plasticity by changing morphology, behavior, reproduction, and physiology to meet the individual¡¦s ability to survive demanding conditions. This study was aimed to investigate the expression of angiotensin receptor and nitric oxide synthase genes of individuals resided at differential altitude, in an attempt to find the role of these molecules in cardiovascular adaptation to altitude. Spiny rats (Niviventer coxingi) are widely elevational distributed in Taiwan. They were studied under more natural conditions to provide an ecological context data on physiological plasticity between the different altitudes. I examined the body weight, blood pressure, heart rate and the expression of angiotensin type 1 or type 2 (ATI or ATII) receptor and nitric oxide synthase (NOS) genes in tissues (cortex, hypothalamus, medulla, lung, heart, aorta, adrenal gland and kidney) of spiny rats resided at differential altitude and during the domesticated period. The results of the study showed that spiny rats resided at higher altitudes were lighter than that at lower altitudes (750 m: 178.6¡Ó35.8 g and 1600 m: 122.3¡Ó29.3 g). Spiny rats resided at 1600 m did not change their body weight during the domesticated period, but rats resided at 750 m gradually reduced their body weight. Blood pressure and heart rate were similar between rats resided at different altitudes, and did not change during the domesticated period. ATI receptor, endothelelial NOS (eNOS), inducible NOS (iNOS) and neuronal NOS (nNOS) mRNA expression in these tissues were similar between rats resided at different altitudes. ATII receptor mRNA expressed in these tissues under our detection limit. Rats resided at 750 m declined the level of nNOS in heart, when they were domesticated at 100 m. ATI receptor in kidney reduced at first, but subsequently increase to same level like native. Moreover, rats resided at 1600 m declined the level of iNOS in heart, when they were domesticated at 100 m. Together, these results indicate that heart rate, blood pressure, ATI receptor, eNOS, iNOS and nNOS mRNA expressions in these tissues were similar between rats resided at different altitudes. If there was no other compensatory mechanism, individuals resided at higher altitude were limited in low available oxygen. A reduced body weight could help in adaptation to high-altitude.

The renin¡Vangiotensin system (RAS) plays a role in the pathogenesis of obesity. Angiotensin-converting enzyme (ACE), the component of the RAS system, has recently been found to be completely expressed in human adipose tissue. Angiotensin II, the active component of RAS, may affect adipogenesis and adipocyte metabolism. Among ACE polymorphism, the gene DD genotype has shown to be regulated with a higher agiotensin- converting enzyme level in plasma. Hence, the purpose of this research is to investigate the correlation of ACE gene polymorphism to body mass index (BMI) between aborigines and Han non-aborigines. The relationship of race and ACE insertion (I)/ deletion (D) polymorphism was also analyzed.The results showed a higher value of ACE DD genotype appeared in aborigines (35.7 %) than that in Han population (10.8 %)(p < 0.0001). BMI in aborigines was 26.4¡Ó4.6 kg/m2, while in Han population was 24.4¡Ó3.6 kg/m2 (P<0.0001). A higher waist circumference value was also found among females aborigines than that found among female in Han population (86.9¡Ó10.7 vs 84.3¡Ó9.7 cm, P<0.0001). Simple and multiple linear regression analyses showed that both race and ACE gene polymorphism are closely correlated to BMI in all subjects. By discussion on the cases for the Han and aborigines population separately, it was found that the ACE gene polymorphism is associated with BMI in Han population it is not significant in aborigines. In aborigines, life style in culture is associated with BMI. In conclusion, ACE gene polymorphism and race were independent factors correlated to BMI, but differences could be found between race and ACE gene polymorphism.

Zugl.: Giessen, Univ., Diss., 2009

Zugl.: Giessen, Universiẗat, Diss., 2009.

Thesis (Ph. D.)--University of Missouri-Columbia, 1999. / Typescript. Vita. Includes bibliographical references. Also available on the Internet.

Thesis (Ph. D.)--University of Missouri-Columbia, 1999. / Typescript. Vita. Includes bibliographical references. Also available on the Internet.

Thesis (Ph.D.)--Brown University, 2008. / Vita. Advisor: Kate L. Lapane. Includes bibliographical references (leaves 64-70).