My laboratory has a long-standing interest in understanding the regulation of peptide hormones (e.g., bradykinin and angiotensin) and their physiological and pathological functions in the cardiovascular system. We have focused on the kallikrein-bradykinin and renin-angiotensin systems, particularly the enzymes that regulate the generation and degradation of these important peptide hormones. For example, we are investigating the structure and function of human carboxypeptidase (CPM), a plasma membrane enzyme we discovered that generates the specific agonist of the kinin G-protein coupled B1 receptor. We have uncovered an important protein-protein interaction between CPM and the B1 receptor that facilitates signaling in two ways. First, it allows efficient delivery of des-Arg-kinin agonist generated by CPM to the B1 receptor. Second, the binding of substrate alone to CPM can allosterically activate the B1 receptor via protein-protein interaction and conformational change to enhance calcium signaling and nitric oxide (NO) production.

Model of GPI-Anchored CPM on the Membrane

In another project, we are delineating the signaling pathways stimulated by the B1 receptor that activate inducible nitric oxide synthase (iNOS) to cause high output NO production in endothelial cells under inflammatory conditions. We have found that high output NO itself has a protective effect on the endothelial barrier. In contrast, in the presence of other inflammatory mediators such as thrombin or superoxide generation, B1 receptor activation of iNOS exacerbates barrier disruption, due to generation of the potent oxidant peroxynitrite. We are also exploring the pathway by which the bradykinin B2 receptor stimulates prolonged, high-output eNOS-dependent NO in cytokine-activated endothelial cells. These studies will identify novel mechanisms by which lung microvascular endothelial cells under inflammatory conditions can generate high-output NO as autocrine and paracrine signals to alter endothelial permeability. It is hoped that these investigations will identify potential targets for therapeutic intervention to improve endothelial barrier function in patients suffering from acute lung injury (ALI) or acute respiratory distress syndrome (ARDS).

*Click on CPN, CPM, or B1 receptor to download related publications

Lab Members