Project Summary
Many forms of cardiovascular disease lead to pathological cardiac hypertrophy, which is maladaptive because
it causes reduced contractility of the heart, resulting in life-threatening heart failure. In contrast, exercise can
cause the heart to grow in a functionally adaptive way; this is defined as physiological cardiac hypertrophy. Our
long-term goal is to achieve a better mechanistic understanding of both forms of heart growth. In this proposal,
we will address this understanding by examining roles for selenium (Se) in cardiac hypertrophy. Se, which is
an essential element in our diet, is well known to be required for cardiovascular health, though the precise role
played by Se the cardiovascular system is not known. A major role for Se in all organs and cells is that it is a
key component of selenoproteins; here, we will examine the function of Se in selenoproteins in the heart. Our
specific objective is to examine the selenoprotein, SelenoS, which we believe to be required for both
pathological and physiological cardiac hypertrophy. We will conduct this investigation in mouse models of
cardiac hypertrophy using molecular genetic approaches to selectively and specifically impair or enhance the
function of SelenoS, followed by studies to determine the effects of these maneuvers on heart structure and
function. One mechanistic point we will be addressing is how Se affects heart growth. However, since there are
23 other proteins in mice that require Se, in order to focus our approach on determining how Se is used by only
SelenoS in the heart, we will examine the effects of a mutant form of SelenoS, SelenoS-Se, which is different
from SelenoS only in that it does not have Se. In this way, we will be able to mechanistically pinpoint how Se
on just SelenoS works to support cardiac growth, because all of the other selenoproteins will still have Se
incorporated into their structures. SelenoS is also involved in the adaptive degradation of misfolded proteins in
the endoplasmic reticulum, a process called ERAD. We will also examine the effects of SelenoS, SelenoS-Se,
and a form of SelenoS that cannot function in ERAD, Seleno-ERAD, on cardiac growth. Our specific aims are
to 1- determine the effects of depleting endogenous SelenoS on cardiac structure, function, gene and protein
expression in mouse models of cardiac hypertrophy, 2- examine the effects of ectopic expression of SelenoS,
Seleno-ERAD and SelenoS-Se in mice in which endogenous SelenoS has been knocked down on pathological
and physiological cardiac hypertrophy, and 3- assess how SelenoS, Seleno-ERAD and SelenoS-Se affect the
structure and function of the ERAD complex.