Grant: Operating Grant

In heart failure, cardiac muscle contraction is negatively altered by a family of molecules called "Protein Kinase C" (PKC). We found that reducing CapZ protein blocks PKC-dependent inhibition of contraction. We hypothesized that reducing CapZ protects hearts against heart failure. Myocardial infarctions or "heart attacks" increase PKC activity in heart muscle cells. Increased PKC activity decreases heart function and damages tissue. We hypothesized that transgenic mice deficient in cardiac CapZ protein are protected against infarctions. Normal mouse hearts exhibited significant damage and dysfunction following infarction, while CapZ transgenic mice had minor tissue damage and significantly better function than mice with normal CapZ levels. We will determine if a peptide that decreases CapZ protects hearts against infarctions. We will also examine how CapZ is controlled during heart attacks, information that may be used to develop new therapies. Coronary artery disease increases PKC activity in the heart. Chronic PKC activation drives hearts into failure by reducing contractility. We hypothesized that reduced CapZ protects against heart failure. A preliminary study found that occluding a coronary artery caused significant dysfunction in normal mice, but by comparison CapZ deficient transgenic mice performed significantly better. We propose to complete this study and examine the potentially protective ability of decreased CapZ throughout heart failure. Reducing CapZ blocks PKC depression of heart contraction through an unknown mechanism. We have created a PKC activation model to identify how CapZ controls PKC. Preliminary studies support the feasibility of our model. We propose experiments to test our hypothesis that decreased CapZ works by blocking the ability of G-proteins to initiate PKC activation. This proposal investigates a novel therapeutic target for heart failure and will determine how CapZ works in heart.