Development of Targeted Pharmacotherapy for Cardiovascular Disease

作者：Katanasaka Yasufumi^*

来源：Journal of the Pharmaceutical Society of Japan, 2017, 137(11): 1349-1353.

DOI：10.1248/yakushi.17-00171

• targeted pharmacotherapy
• cardiovascular disease
• heart failure
• p300/GATA4 transcriptional pathway
• receptor for activated protein kinase C1

Heart and cardiovascular diseases are the leading causes of death in the world. Heart failure (HF) in particular is becoming a serious widespread medical issue, especially following various stresses such as myocardial infarction and hemodynamic overload. One pathological cardiac change in HF is left ventricular hypertrophy (LVH). LVH is associated with increased risk for HF; however, no drug therapy for LVH has yet been developed. During the development of LVH, gene expression is altered in cardiomyocytes through transcription factors, co-activators, and histone modifications. A zinc-finger protein and cardiac-specific transcription factor, GATA4, forms a large complex with functional proteins, including an intrinsic histone acetyltransferase, p300. p300 serves as a co-activator of GATA4 and is required for GATA4-dependent gene transcription. Although the p300/GATA4 pathway is involved in pathological cardiac hypertrophy, the remaining signal transduction pathways involved in pathological cardiac changes remain unclear. To identify therapeutic targets for preventing HF, GATA4-binding proteins have been analyzed, and 73 proteins were identified by tandem affinity purification and mass spectrometry. Here, we describe a receptor for activated protein kinase Cl (RACK1) as a novel GATA4-binding protein. RACK1 inhibited phenylephrine (PE)-induced cell hypertrophy and hypertrophy-associated gene transcription in cultured cardiomyocytes. Tyrosine phosphorylation of RACK1 was enhanced, and binding between GATA4 and RACK1 was disrupted in cardiomyocytes of hypertensive rats. In addition, tyrosine phosphorylation of RACK1 disrupted the RACK1/GATA4 complex. These findings suggest that clarification of nuclear signal pathways in cardiomyocytes would help to identify therapeutic targets for HF.

• 出版日期2017-11