JJ. Low molecular weight fibroblast growth factor-2 signals via protein kinase C and myofibrillar proteins to protect against postischemic cardiac dysfunction. Am J Physiol Heart Circ Physiol 304: H1382-H1396, 2013. First published March 11, 2013 doi:10.1152/ajpheart.00613.2012.-Among its many biological roles, fibroblast growth factor-2 (FGF2) acutely protects the heart from dysfunction associated with ischemia/reperfusion (I/R) injury. Our laboratory has demonstrated that this is due to the activity of the low molecular weight (LMW) isoform of FGF2 and that FGF2-mediated cardioprotection relies on the activity of protein kinase C (PKC); however, which PKC isoforms are responsible for LMW FGF2-mediated cardioprotection, and their downstream targets, remain to be elucidated. To identify the PKC pathway(s) that contributes to postischemic cardiac recovery by LMW FGF2, mouse hearts expressing only LMW FGF2 (HMWKO) were bred to mouse hearts not expressing PKC␣ (PKC␣KO) or subjected to a selective PKCε inhibitor (εV1-2) before and during I/R. Hearts only expressing LMW FGF2 showed significantly improved postischemic recovery of cardiac function following I/R (P Ͻ 0.05), which was significantly abrogated in the absence of PKC␣ (P Ͻ 0.05) or presence of PKCε inhibition (P Ͻ 0.05). Hearts only expressing LMW FGF2 demonstrated differences in actomyosin ATPase activity as well as increases in the phosphorylation of troponin I and T during I/R compared with wild-type hearts; several of these effects were dependent on PKC␣ activity. This evidence indicates that both PKC␣ and PKCε play a role in LMW FGF2-mediated protection from cardiac dysfunction and that PKC␣ signaling to the contractile apparatus is a key step in the mechanism of LMW FGF2-mediated protection against myocardial dysfunction. low molecular weight FGF2; PKC␣ and ε; troponin; actomyosin ATPase; postischemic cardiac function CARDIOVASCULAR DISEASE IS the number one killer in the U.S., and every year over eight million people in the U.S. suffer from myocardial infarction (43). Often, myocardial ischemia is characterized by lowered postischemic left ventricular function, which is associated with increased morbidity and mortality (7). There is a profound and immediate need to address the problem of myocardial dysfunction and infarction associated with cardiac ischemia and reperfusion (I/R). One promising therapeutic strategy to alleviate I/R-induced cardiac injury is fibroblast growth factor-2 (FGF2).FGF2, found at elevated levels in the serum of I/R patients (63), has both angiogenic and acute cardioprotective effects (6,26,37,54,64). This makes FGF2 an outstanding candidate for the treatment of cardiac patients; however, while in recent years, there have been a number of noteworthy developments characterizing the mechanism of action of FGF2 in the ischemic heart, there are several unanswered questions that must be addressed before FGF2 becomes a therapeutic molecule. Yet to be determined is the distinct role each FGF2 isoform plays in the ischemic heart. FGF2...