Atheroprotection by smooth muscle selective RhoGAPs

1.总结 动脉粥样硬化是世界范围内发病率和死亡率的主要原因。很明显， 肌细胞（SMCs）在斑块进展和稳定性中起着关键作用，但仍存在许多问题， 关于保护性纤维帽内表型调节的SMC的来源、命运和功能， 和坏死的核心SMC功能缺陷导致高血压（HTN）和血管僵硬度增加 还通过改变血管壁内的机械信号传导来影响斑块形成和进展。虽然 这些生理参数是主要的独立的心血管危险因素，我们所知甚少 关于它们的发展，它们的相互关系，或它们促进动脉粥样硬化的机制。 我们之前已经证明SMC选择性Rho特异性GAP，GRAF3，降低小鼠血压， 通过限制阻力小动脉中RhoA依赖的SMC收缩性， rs604723作为该基因中BP相关基因座内的致病变体。我们最近的数据表明， GRAF信号传导具有动脉粥样硬化保护作用，并抑制收缩和细胞外基质基因的表达 以及促炎和促钙化基因程序， 动脉粥样硬化斑块发展和破裂。本提案的总体目标是评估以下方面的作用： GRAF3基因型对大型和多样化心血管疾病患者心血管结局的影响 群体，以直接测量GRAF信号传导对动脉粥样硬化和血管硬化的贡献， 并利用我们对GRAF分子内相互作用的理解来鉴定GRAF激活化合物， 可用于治疗HTN和动脉粥样硬化疾病。

1. Summary Atherosclerosis is a leading cause of morbidity and mortality world-wide. It is clear that vascular smooth muscle cells (SMCs) play a critical role in plaque progression and stability, but many questions remain in regard to the source, fate, and function of the phenotypically modulated SMCs within the protective fibrous cap and necrotic core. Defects in SMC function that lead to hypertension (HTN) and increased vascular stiffness also affect plaque formation and progression by altering mechanical signaling within the vessel wall. Although these physiologic parameters are major independent cardiovascular risk factors, we know surprisingly little about their development, their inter-relationship, or the mechanisms by which they promote atherosclerosis. We have previously shown that the SMC-selective Rho-specific GAP, GRAF3, reduces blood pressure in mice and humans by limiting RhoA-dependent SMC contractility in resistance arterioles and went on to identify rs604723 as the causal variant within the BP-associated locus in this gene. Our more recent data indicate that GRAF signaling is atheroprotective and inhibits the expression of the contractile and extracellular matrix genes that drive vascular stiffness, and the pro-inflammatory and pro-calcification gene programs that contribute to atherosclerotic plaque development and rupture. The overall goals of this proposal are to assess the role of GRAF3 genotype on cardiovascular outcomes in a large and diverse cardiovascular disease patient population, to directly measure the contribution of GRAF signaling to atherosclerosis and vascular stiffening, and to use our understanding of GRAF intra-molecular interactions to identify GRAF-activating compounds that could be useful for treating HTN and atherosclerotic disease.