UCSF DIABETES, ENDOCRINOLOGY & METABOLISM TRAINING PROGRAM FACULTY RESEARCH SUMMARIES

Hormonal Regulation of Growth and Hypertrophy in the Cardiovascular and Renal Systems

Our laboratory is interested in defining the molecular determinants that govern expression of the natriuretic peptide genes in myocardial cells and the genes encoding their receptors in vascular and renal cells. Two natriuretic peptide hormones are produced in the heart. Atrial natriuretic peptide (ANP) is preferentially expressed in the atrial vs. ventricular myocytes of the neonatal rat heart while brain natriuretic peptide (BNP) is expressed predominantly in the cardiac ventricle. Each of these genes is typically expressed at a very low level in adult ventricular myocardium; however, under conditions which promote hypertrophy of the heart (e.g. high blood pressure or congestive heart failure), ventricular expression of both genes increases dramatically. Using a variety of biochemical and mechanical stimuli to induce hypertrophy in cultured neonatal rat cardiac myocytes, we are attempting to define the molecular mechanisms which link the hypertrophic stimulus to enhanced expression of these marker genes. We hope to use this information to develop strategies for uncoupling the mechanism and controlling the hypertrophic response.

Receptors for the NPs can be divided into two major classes. The first, which includes natriuretic peptide receptors (NPR) A and B, possesses particulate guanylyl cyclase activity. These receptors are believed to mediate most of the biologically important effects of the peptides. The second category includes NPR-C, a single transmembrane domain receptor with a truncated intracellular domain. This receptor seems to operate in a clearance mode in vivo, although there is growing evidence that it also possesses signaling activity. We are in the process of identifying the molecular determinants that govern transcriptional activity of the promoters linked to each of these three genes. Both NPR-A and B, and possibly NPR-C, possess growth suppressant activity in cardiac fibroblasts and in vascular endothelial and smooth muscle cells. A better understanding of these growth suppressant properties may provide important insights into the pathophysiology of disorders affecting the vascular wall or myocardial interstitium.

Selected References

Liang, F., Webb, P., Marimuthu, A., Zhang, S. and Gardner, D.G. Triiodothyronine increases BNP gene transcription and amplifies endothelin-dependent BNP gene transcription and hypertrophy in neonatal rat ventricular myocytes. J. Biol. Chem. 278: 15073-15083 (2003).

Anderson, H.D., Wang, F. and Gardner, D.G. Role of the epidermal growth factor receptor in signaling strain-dependent activation of the brain natriuretic peptide gene. J. Biol. Chem. 279: 9287-9297 (2004).

Chen, S. and Gardner, D.G. Suppression of the inhibitory kinases WEE1 and MYT1 correlates with endothelin-dependent proliferation of rat aortic smooth muscle cells. J. Biol. Chem. 279: 13755-13763 (2004).

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