Abstract Cardiac pathologies, including ventricular hypertrophy, are the primary cause of death in industrialized countries. Cardiac hypertrophy is often the consequence of work overload on the heart and characterizes several cardiovascular diseases, including atherosclerosis and hypertension. Cardiac hypertrophy is accompanied by genetic reprogramming characterized by the reexpression of several embryonic and growth response genes. Two of these genes encode A- and B-type natriuretic peptides (ANP and BNP), two cardiac-specific hormones secreted by myocytes, which play an important role in blood pressure regulation. The aim of the present study was to study the effect of acute pressure overload on BNP gene expression in the hearts of normal and hypertensive rats and then to examine the role of a passerine factor, angiotensin II (Ang II), on volume and pressure overload -induced ANP and BNP secretion and synthesis. Further, the aim was to characterize elements on the BNP promoter mediating hemodynamic stress in vivo. BNP gene expression was studied in conscious spontaneously hypertensive (SHR) rats and together with ANP in two hypertensive, ream Transgenic rat models. The increased workload of the heart was produced by the infusion of vasopressin (AVP), phenylephrine (PHE) or bolus saline infusion. The increased workload caused rapid increases in cardiac BNP mRNA levels. Daring both AVP and PHE infusions, substantial increases in ventricular BNP mRNA levels were already evident after I h, and peak levels of BNP mRNA were reached at 4 h. Transgenic rats carrying one extra mouse renin gene showed impaired secretion and synthesis of ANP and BNP, while double transgenic rats carrying both human angiotensinogen and human renin genes showed augmentation of left atrial, but not ventricular BNP gene expression in response ta acute pressure overload. To characterize the elements mediating hemodynamic stress, bi-lateral nephrectomy was performed. GATA motif transduced the hemodynamic stress stimulus 26–28 hrs postnephrectomy in BNP gene expression.In conclusion, these results show that pressure overload abruptly stimulates the cardiac expression of a noncontractile protein gene BNP, suggesting that it may be used as a myocyte-specific marker of mechanical loading. BNP gene expression was augmented in atria hut nut in ventricles in response to pressure overload in an experimental model of hypertension, suggesting that high local levels of Ang II may differentially regulate cardiac gene expression in atrial and ventricular myocytes in double transgenic rats. At the transcriptional level, acute hemodynamic stress produced by nephrectomy increases BNP reporter expression through a GATA-dependent pathway.

<p>Cellular structural mechanics play a key role in homeostasis by transducing mechanical signals to regulate gene expression and by providing adaptive structural stability for the cell. The alteration of nuclear mechanics in various laminopathies and in natural aging can damage these key functions. Arterial endothelial cells appear to be especially vulnerable due to the importance of shear force mechanotransduction to structure and gene regulation as is made evident by the prominent role of atherosclerosis in Hutchinson-Gilford progeria syndrome (HGPS) and in natural aging. Computational models of cellular mechanics may provide a useful tool for exploring the structural hypothesis of laminopathy at the intracellular level. This thesis explores this topic by introducing the biological background of cellular mechanics and lamin proteins in arterial endothelial cells, investigating disease states related to aberrant lamin proteins, and exploring computational models of the cell structure. It then presents a finite element model designed specifically for investigation of nuclear shear forces in arterial endothelial cells. Model results demonstrate that changes in nuclear material properties consistent with those observed in progerin-expressing cells may result in substantial increases in stress concentrations on the nuclear membrane. This supports the hypothesis that progerin disrupts homeostatic regulation of gene expression in response to hemodynamic shear by altering the mechanical properties of the nucleus.</p>