Project Summary
Hypertensive and ischemic heart diseases are the two most important risk factors of heart failure. In
response to elevated blood pressure, the heart manifests hypertrophic growth to ameliorate ventricular wall
stress. This once adaptive response may decompensate and progress into heart failure. On the other hand,
myocardial infarction causes significant structural damage of the heart. The common clinical practice to treat
cardiac ischemia via restoration of coronary arteries leads to additional reperfusion injury. Insults from ischemia
and reperfusion together significantly weaken the pumping function of the heart. Despite extensive interests and
urgent clinical needs, our understanding of the mechanisms for heart failure development remains limited.
Pathological cardiac remodeling is a common route of both hypertensive and ischemic heart diseases. In
response to either elevated demand or cardiac damage, the heart mounts an acute reaction to compensate for
the loss of cardiac contractility. Under persistent stress, however, decompensation occurs and heart failure
develops. Previous studies have shown that metabolic alteration precedes most if not all other changes during
pathological cardiac remodeling. However, the contribution and mechanism of metabolic remodeling in heart
failure is still elusive.
Preliminary results here show that de novo pyrimidine biosynthesis is acutely and significantly augmented
in the heart in response to pressure overload, preceding structural and electrophysiological alterations. Moreover,
Cad (carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase) as the rate-limiting
enzyme of this pathway is strongly induced. On the other hand, de novo pyrimidine biosynthesis is also
upregulated by reperfusion after ischemia. Based on previous findings and these pilot data, a hypothesis of
pyrimidine biosynthesis in pathological cardiac remodeling has been formulated. Both gain-of and loss-of-
function mouse models have been generated that will be employed to test 1) the role of Cad and de novo
pyrimidine biosynthesis in pressure overload-induced cardiomyopathy, 2) the role of Cad and de novo pyrimidine
in cardiac ischemia/reperfusion-caused pathological cardiac remodeling, and 3) the feasibility of using a Cad
inhibitor to arrest heart failure development under hypertensive and ischemic heart disease conditions. In vitro
experiments using primary cardiac myocyte culture will be performed to corroborate the in vivo tests. Elucidation
of the role of de novo pyrimidine biosynthesis during pathological cardiac remodeling and heart failure will
advance our understanding of the pathophysiology of hypertensive and ischemic heart diseases and pave a way
for novel, more effective therapeutic design.