Welcome to the Yan Lab

Our research interests are in the field of cyclic nucleotide signaling and cardiovascular biology, with a particular focus on cyclic nucleotide phosphodiesterases (PDEs) that catalyze the hydrolysis of cyclic nucleotide second messengers (cAMP and cGMP). The versatility and specificity of cyclic nucleotide signaling is achieved through specific compartmentalization of different cyclic nucleotide pools that are controlled by distinct PDE isoforms. PDEs have been proved to be a highly promising class of therapeutic targets for drug development, as best exemplified by PDE5-specfic inhibitor, Viagra. Dysregulation of PDE expression/activation have been implicated in a number of diseases. Our research programs have been among the pioneers in elucidating the function, regulation, and underlying mechanism of different PDE activation/ inhibition in the pathogenesis of cardiovascular diseases. We aim to reveal new molecular targets for pharmacologic modulation of specific cyclic nucleotide signaling in the treatment of cardiovascular diseases.

There are two primary areas of researches in our laboratory:

Regulation and function of PDE in vascular smooth muscle cell (SMC) and vascular disorders. Vascular SMCs exist in diverse phenotypes and exhibit phenotypic plasticity, e.g. changing from a quiescent/contractile phenotype to an active, myofibroblast-like, frequently called a “synthetic” phenotype. Synthetic SMCs gain the ability to proliferate, migrate, secrete extracellular matrix (ECM) proteins/proteases, and mediate inflammatory response. SMC phenotype switching is critical in the development of various vascular disorders, such as hypertension, intima/media thickening (Figure 1), atherosclerosis and aortic aneurysms. To understand the specific cyclic nucleotide signaling responsible for SMC phenotypic alteration, we have performed initial discovery screening for PDE isozymes that are differentially expressed in contractile versus synthetic SMCs. Through genetic depletion and pharmacological inhibition, we aim to demonstrate the causative role and address the underlying mechanism of these PDEs in SMC pathology and vascular remodeling using in vitro and in vivo approaches.??

Figure 1: Representative Verhoeff-van Gieson staining images of uninjured vessels (left) and injured vessels from mice subjected to left femoral artery with wire injury(right).

• Role of PDE in pathological cardiac remodeling and heart failure. cAMP and cGMP regulate a wide variety of cardiac functions, from the short-term effects on myocyte contraction/ relaxation to long-term effects such as gene expression and structural remodeling (Figure 2). To identify the PDE isozymes altered in disease hearts, we have performed initial screening for PDEs that are altered in diseased hearts.  The expression of a number of PDE isozymes is changed: some are up-regulated and some are down-regulated. The ongoing and future studies are aimed to determine the role and mechanism of these altered PDEs in cardiac remodeling and dysfunction through genetic and pharmacological approaches.

  

  Figure 2: Representative picrosirius Red staining images of heart sections from mice subjected to sham (left) and transverse aortic constriction (TAC) (right). Red staining shows fibrotic area.

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