Contact Info David Gardner, MD UCSF Diabetes Center 513 Parnassus Ave. HSW 1109, Box 0540 San Francisco, CA 94143 Tel: (415) 476-2729 Fax: (415) 564-5813   Email: dgardner@diabetes.ucsf.edu

Professor in Residence

My laboratory is interested in defining the molecular determinants which govern the expression of the natriuretic peptide genes in the myocardial cell and the genes encoding their receptors in target tissues.
Two natriuretic peptide hormones are produced in the heart. Atrial natriuretic peptide (ANP) is preferentially expressed in the atrial myocyte while brain natriuretic peptide (BNP) is expressed nearly equivalently in atrial vs. ventricular myocytes. Each of these genes is typically quiescent in adult ventricular myocardium; however, under conditions which promote hypertrophy of the heart (e.g. diabetes, high blood pressure or congestive heart failure), ventricular expression of both genes increases dramatically. Using a number of different biochemical and mechanical stimuli, we are attempting to define the molecular mechanism(s) which links the hypertrophic stimulus to enhanced expression of these marker genes in the ventricular myocyte. With this information in hand we can attempt to develop strategies for uncoupling the mechanism and controlling the hypertrophic response.

Receptors for the NP can be divided into two major categories.The first category, representing natriuretic peptide receptors (NPR) A and B, is covalently linked to the particulate guanylyl cyclase and is 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 have recently identified a role for the SP-1 and CCAAT transcription factor families in regulating basal expression of both the NPR-A and NPR-B genes and we are presently assessing the role of each in signaling regulated expression by environmental factors like osmotic stress. Pathological states like congestive heart failure and nephrosis, common complications of diabetes mellitus, are typically characterized by resistance to the biological effects of the NP. At least a portion of this resistance appears to reflect changes in the production and/or sensitivity of the NPR in target cells at the periphery. Our ultimate goal is to define how malregulation of these genes might contribute to the resistance seen in these clinical syndromes.

Selected Publications:

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.

Chen, S. and Gardner, D.G. Osmoregulation of natriuretic peptide receptor signaling in inner medullary collecting duct. A requirement for p38 MAPK. J. Biol. Chem. 277: 6037-6043, 2002.

Kovacic-Milivojevic, B., Roediger, F., Almeida, E.A.C., Damsky, C.H., Gardner, D.G. and Ilic, D. Focal adhesion kinase mediates both sarcomeric organization and transcriptional activation of genes associated with cardiac myocyte hypertrophy. Mol. Biol. Cell. 12: 2290-2307, 2001.