| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2006: ¥2,000,000 (Direct Cost: ¥2,000,000)
Fiscal Year 2005: ¥1,500,000 (Direct Cost: ¥1,500,000)
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| Research Abstract |
The importance of Ca entry in the cardiac hypertrophic response is well documented, but the actual Ca entry channels remain unknown. Transient receptor potential (TRP) proteins are thought to form Ca entry channels that are involved in the proliferation various cells. The purpose of this study was to explore the potential involvement of TRP channels in the development of cardiac hypertrophy. EMSA revealed an interaction between NRSF (neuron restrictive silence factor) and a NRSE-like sequence in TRPC1 genomic DNA. We found that TRPC1 was up-regulated in dnNRSF-Tg mice heart which mimick dilated cardiomyopathy. These results suggest that TRPC1 has the character of fetal cardiac gene and reexpresses in the cardiomyopathy. Although TRPs C1, C3, C5, and C6 were constitutively expressed, only TRPC1 expression was significantly increased in the hearts of abdominal aortic-banded rats compared to sham-operated rats. Using primary cultures of neonatal rat cardiomyocytes, we detected increases i
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n the expression of TRPC1, brain natriuretic peptide (BNP), and atrial natriuretic factor (ANF), as well as increases in store-operated Ca entry (SOCE) and cell surface area, following endothelin-1 (ET-1) treatment. Silencing of the TRPC1 gene via small interfering RNA (siRNA) attenuated SOCE and prevented ET-1-, angiotensin-II (AT II)-, and phenylephrine (PE)-induced cardiac hypertrophy. In HEK 293T cells, overexpression of TRPC1 augmented SOCE, leading to an increase in nuclear factor of activated T cells (NFAT) promoter activity, while co-transfection with dominant-negative forms of TRPC1 suppressed it. Mreover, we examined the involvement of TRPC1 in the vascular smooth muscle cell hypertrophy. We demonstrate Ang II and subsequent NF-kappaB activation induces hCASMC hypertrophy through an enhancement of TRPC1 expression. In conclusion, TRPC1 functions in Ca influx, and its upregulation is involved in the development of cardiac and vascular hypertrophy ; moreover, it plays an important role in the regulation of the signaling pathways that govern cardiac and vascular hypertrophy. Less
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