The heart responds to injury and chronic pressure overload by pathologic growth 
and remodeling, which frequently result in heart failure and sudden death. 
Calcium-dependent signaling pathways promote cardiac growth and associated 
changes in gene expression in response to stress. The 
calcium/calmodulin-dependent phosphatase calcineurin, which signals to nuclear 
factor of activated T cells (NFAT) transcription factors, serves as a transducer 
of calcium signals and is sufficient and necessary for pathologic cardiac 
hypertrophy and remodeling. Transient receptor potential (TRP) proteins regulate 
cation entry into cells in response to a variety of signals, and in skeletal 
muscle, expression of TRP cation channel, subfamily C, member 3 (TRPC3) is 
increased in response to neurostimulation and calcineurin signaling. Here we 
show that TRPC6 was upregulated in mouse hearts in response to activated 
calcineurin and pressure overload, as well as in failing human hearts. Two 
conserved NFAT consensus sites in the promoter of the TRPC6 gene conferred 
responsiveness to cardiac stress. Cardiac-specific overexpression of TRPC6 in 
transgenic mice resulted in heightened sensitivity to stress, a propensity for 
lethal cardiac growth and heart failure, and an increase in NFAT-dependent 
expression of beta-myosin heavy chain, a sensitive marker for pathologic 
hypertrophy. These findings implicate TRPC6 as a positive regulator of 
calcineurin-NFAT signaling and a key component of a calcium-dependent regulatory 
loop that drives pathologic cardiac remodeling.