Objective: Heme oxygenase-1 (HO-1) has been well established as a cytoprotective molecule, and has been shown to exert cardioprotective effects in both hypertension and cardiac hypertrophy. However, the precise mechanism of the cardioprotective effect of HO-1 has yet to be fully elucidated. The natriuretic peptide system (NPS) is also a key player in cardiovascular homeostasis and tissue dynamics, and has also been shown to be cardioprotective in a variety of pathologic conditions. This study examined the effect of high dietary salt treatment in genetic models of HO-1, and assessed the expression of the NPS in the left ventricle (LV), in order to gain insight into the relationship between varying levels of HO-1 expression with the development of cardiac hypertrophy and the expression of the NPS. Methods: Age-matched 12-week old male HO-1 knockout (HO-1-/-) and HO-1 cardiomyocyte-specific transgenic overexpressing (HO-1Tg) mice were treated with either normal salt (NS; 0.8%) or high salt (HS; 8.0%) chow for 5 weeks. LV mRNA expression was determined using quantitative real-time RT-PCR. Results: HO-1-/- mice fed HS diet had significantly higher left ventricle-to-body weight ratio (LV/BW) compared to HO-1+/+ mice fed NS diet. HO-1-/- mice had significantly reduced expression of the NPS compared to controls, and these mice did not exhibit a salt-induced increase in ANP expression. HS treatment had no effect on LV/BW in HO-1Tg mice compared to controls. HO-1Tg mice had significantly higher ANP and BNP expression compared to controls. Conclusions: The presence of HO-1 is required for normal salt-induced changes in the local cardiac NPS. HO-1 ablation resulted in significantly lower mRNA expression of the NPS, whereas HO-1 overexpression resulted in higher mRNA expression of the NPS. These data indicate that the detrimental effect of reduced HO-1 expression and the cardioprotective effect of increased HO-1 expression may be due, in part, to altered expression of the NPS. / Thesis (Master, Anatomy & Cell Biology) -- Queen's University, 2009-10-20 09:15:20.541

The natriuretic peptide system (NPS) is a hormonal system critical to mammalian cardiovascular homeostasis. The purpose of the present study was to investigate the role of ANP during early postnatal cardiac development by i) monitoring the development of cardiac hypertrophy during early postnatal development of the ANP-/- mice, and ii) comparing morphologic, morphometric and molecular differences in ANP+/+ mice compared to ANP-/- mice during this developmental period. Age matched male ANP+/+ and ANP-/- mice, aged day 1 and weeks 1 to 5, were evaluated. Body weight, organ weights and hematocrit were recorded. RNA was isolated and quantitative real-time RT-PCR was used to monitor cardiac gene expression. An additional cohort of animals was used for morphologic and morphometric analysis. Heart weight to body weight ratio (HW/BW) was dramatically higher in ANP-/- animals at all time points, indicating cardiac hypertrophy is established before the advent of adult blood pressure. Molecular analysis of gene expression revealed a compensatory response of the NPS in the ANP-/- mice. Specifically an up-regulation of BNP expression in ANP-/- mice was noted throughout postnatal development. Similarly, NPR-A and NPR-C demonstrated compensatory action for the lack of ANP, as expressional levels also varied throughout development. Morphological analysis of cardiac vasculature revealed striking structural differences between ANP+/+ and ANP-/- mice. Quantitative stereological analysis of LM images indicated a greater vessel volume in ANP-/- compared to ANP+/+ mice. This study demonstrates that alterations in early molecular events, such as changes in NPS expression, may be responsible for the maintenance and progression of cardiac hypertrophy during early postnatal development in the ANP-/- mice. The absence of ANP during this critical period of development has a profound impact on final cardiac structure leading to future pathological states. / Thesis (Master, Anatomy & Cell Biology) -- Queen's University, 2010-02-05 14:15:33.982

Introduction: Developmental origins of disease refers to the theory that adverse maternal environments influence fetal development and the risk of cardiovascular disease (CVD) in adulthood. To test the hypothesis that gestational hypertension influences the development of CVD in offspring, a novel experimental paradigm was developed using atrial natriuretic peptide gene disrupted mice (ANP-/-). The objective of this thesis was to determine the effect of gestational hypertension on cardio-renal function in offspring. Methods: ANP+/+ females were crossed with ANP-/- males (yielding ANP+/-WT offspring) and ANP-/- females with ANP+/+ males (yielding ANP+/-KO offspring). Previous work has established that ANP-/- dams are hypertensive during pregnancy. Offspring gene expression was measured using qPCR. Offspring arterial blood pressure (BP) was measured with a non-invasive tail cuff system. Offspring left ventricular (LV) function was examined using echocardiography (ECHO). Offspring were treated with normal salt (NS) or high salt (HS) chow for five weeks to assess salt-sensitivity. Daily injections of isoproterenol (ISO) were used to induce cardiac stress in offspring. Collagen deposition was assessed using Masson’s trichrome and picrosirius red staining. Results: Absence of maternal ANP had no effect on either litter size or offspring growth, but caused significant LV hypertrophy in offspring, with no change in LV function. Treatment with ISO resulted in myocardial fibrosis and significant LV diastolic dysfunction with a restrictive filling pattern (increased E/A ratio and E/e’) only in ANP+/-KO offspring. Furthermore, absence of maternal ANP was associated with salt-resistant BP in offspring. Conclusions: Gestational hypertension using the ANP-/- mouse model results in a salt-resistant phenotype in offspring, as well as significant cardiac hypertrophy and an adverse response to activation of the sympathetic nervous system in adult offspring. These data suggest that adverse maternal environments may increase the risk of cardiovascular disease in offspring later in life. / Thesis (Ph.D, Anatomy & Cell Biology) -- Queen's University, 2012-09-18 16:12:01.147

No description available.

Thesis (M.S.)--Cornell University, May, 2008. / Vita. Includes bibliographical references (leaves 102-120).

Thesis (Ph. D.)--University of Hong Kong, 1998. / Includes bibliographical references (leaves 134-161).

Universiẗat, Diss., 2004--München.

Thesis (Ph.D.) - University of Queensland, 2006. / Includes bibliography.

Abstract Adrenomedullin (AM) is a 52-amino acid peptide which is produced in many tissues, including adrenal medulla, lung, kidney and heart. Intravenous administration of AM causes a long-lasting hypotensive effect, accompanied with an increase in the cardiac output in experimental animals. This study was aimed to examine whether AM has any direct effects on myocardial function. In addition to the myocardial contractility, the effects of AM on coronary vascular tone and A-type natriuretic peptide (ANP) release from atria and B-type natriuretic peptide (BNP) gene expression in the ventricles were studied in the perfused rat heart preparation. In spontaneously beating hearts, AM had no effects on the heart rate, but dose-dependently increased the developed tension (DT) with an EC50 of 7 x 10-11 nmol/l, reflecting a potent positive inotropic effect. The lower the initial resting tension, the higher was the elevation in DT. In paced hearts, a protein kinase A inhibitor, H-89, had no effect on AM-induced inotropic effect, and AM did not increase the cAMP content of the ventricular myocardium. In contrast, the inhibitors of sarcoplasmic reticulum Ca2+ stores, ryanodine and thapsigargin, as well as a protein kinase C inhibitor, staurosporine, significantly attenuated the inotropic response to AM. L-type Ca2+ channel blocker, diltiazem, also suppressed the AM-induced elevation in DT. Moreover, AM increased the duration of myocyte action potentials between 10 mV and - 50 mV in isolated rat atria, consistent with an increase in L-type Ca2+ channel current during the plateau. Inotropic effect of endothelin-1 (ET-1), another locally acting peptide, was enhanced by inhibiting the myocardial nitric oxide (NO) synthesis by Nω-nitro-L-arginine methyl ester (L-NAME) in perfused rat heart. The AM-induced inotropic action was unaltered by L-NAME treatment. When AM and ET-1 were administrated in combined infusion, the inotropic response was significantly smaller than that following the infusion of the peptides alone. This attenuated response was more than overcome by infusion of L-NAME, although the individual responses to AM and ET-1 were not modulated by L-NAME at the doses used in the combination. Consistent with its vasodilator action, AM dose-dependently dilated the coronary arteries of the perfused heart. The effect of AM was not dependent on NO under basal conditions or in coronary arteries constricted with ET-1. Furthermore, AM enhanced the stretch-induced release of ANP from the right atrium, but did not affect the ventricular BNP expression induced by ET-1. In conclusion, AM exerts regulatory actions on the heart by increasing cardiac contractility, dilating coronary arteries and modulating stretch-induced ANP release. The inotropic effect of AM was independent of cyclic AMP, but may involve activation of protein kinase C, Ca2+ influx through L-type Ca2+ channels and the release of Ca2+ from the sarcoplasmic reticulum. Endogenous NO production did not modulate the inotropic effect of AM, although the effect of ET-1 was suppressed. Combined administration of AM and ET-1 produced a weak inotropic response most likely because of a potentiated synthesis of NO. Finally, AM had a coronary vasodilator effect and augmented the stretch-induced ANP release in the right atrium.

Abstract Heart responds to pathological hemodynamic stress by increasing cardiac myocyte size, reprogramming gene expression and enhancing contractile protein synthesis. Neurohumoral factors mediate hypertrophic adaptation either directly via specific receptors or indirectly by increasing blood pressure and cardiac load. The aim of this study was to evaluate the role of angiotensin II (Ang II) in the atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) gene expression during cardiac overload. Furthermore, the mechanisms of action of Ang II in regulating cardiac gene expression were studied. Hemodynamic stress was produced by Ang II or nitric oxide (NO) synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME) administration in conscious rats. Despite hypertension and increased left ventricular ANP and BNP mRNA levels, L-NAME administration for 8 weeks did not induce left ventricular hypertrophy. Ang II type 1 receptor (AT1) antagonism decreased significantly L-NAME-induced hypertension and ventricular ANP gene expression. Ang II-induced cardiac overload produced significant increase in ventricular ANP and BNP mRNA levels at 12 and 72 h, respectively. To study whether the factors synthesized by adrenals modulate the response of Ang II, the effects of adrenalectomy were studied. In Ang II-treated rats, adrenalectomy either abolished or blunted the early activation of ANP and BNP gene expression, respectively. Ang II infusion for 2 weeks increased cardiac mass and blood pressure measured by telemetry, and produced changes in diastolic function detected by echocardiography. By using direct plasmid DNA injections into the rat myocardium, BNP promoter activity was observed to increase at 2 h and remain up-regulated up to 2 weeks of Ang II infusion, except at 12 h. BNP mRNA levels increased at 2 h but decreased to basal levels after 72 h. Mutation of GATA elements of the BNP promoter and DNA binding assays revealed that GATA4 mediates the Ang II-responsiveness of the BNP gene. These results indicate that Ang II plays an important role in regulating natriuretic peptide gene expression during cardiac overload. ANP and BNP gene expression in the rat heart is modulated by the adrenal factors during Ang II-stimulated hemodynamic stress and the AT1 receptor antagonism in NO-deficient hypertension. Moreover, ventricular BNP gene expression in Ang II-induced hypertension in vivo is controlled by posttranscriptional mechanisms and GATA elements.