Aging does not lead to myocyte cell loss and myocyte cellular reactive hypertrophy in women, indicating that gender differences may play a significant role in the detrimental effects of the aging process on the heart.

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Rationale: Nerve growth factor (NGF) promotes angiogenesis and cardiomyocyte survival, which are both desirable for postinfarction myocardial healing. Nonetheless, the NGF potential for cardiac repair has never been investigated. Objective: To define expression and localization of NGF and its high-affinity receptor TrkA (tropomyosin-related receptor A) in the human infarcted heart and to investigate the cardiac roles of both endogenous and engineered NGF using a mouse model of myocardial infarction (MI). Key Words: myocardial infarction Ⅲ angiogenesis Ⅲ gene therapy Ⅲ apoptosis M yocardial infarction (MI) remains a major cause of morbidity and mortality and it is responsible for about one third of heart failure cases worldwide. 1 Sudden occlusion of a major coronary artery and acute myocardial ischemia causes rapid death of cardiomyocytes and vascular cells in the area of interest. 2 Loss of cardiomyocytes and vasculature leads to progressive fibrous replacement of myocardium, hypertrophic growth of the spared myocardium, and left ventricular (LV) dilatation. Maladaptive ventricular remodeling contributes to post-MI heart failure, 3 and prognosis of heart failure patients is still poor. 4 Myocardial ischemia triggers a spontaneous angiogenic response aimed at reestablishing myocardial blood flow. Nonetheless, this protective response is usually not sufficient. 5 Nerve growth factor (NGF) is a secreted glycoprotein of the neurotrophin family. NGF elicits its biological effects mainly by binding the high-affinity TrkA receptor (tropomyosin-related receptor A, which is a tyrosine kinase). We and others previously demonstrated that NGF, via TrkA, promotes angiogenesis and endothelial cells (ECs) survival through a mechanism involving the serine/threonine kinase Akt (also known as protein kinase B). 6,7 Akt regulates a variety of cellular functions and it is strongly implicated in angiogenesis and cell survival. 8 We also demonstrated that cultured cardiomyocytes express TrkA and release NGF. 9 Moreover, NGF is an autocrine prosurvival factor for the cardiomyocyte through the Akt/Forkhead box-O transcription factors (Foxo) pathway. 9 Foxo factors stimulate cell death and are downstream targets of Akt. 10 Akt-mediated phosphorylation regulates Foxo-3a subcellular localization and activity: unphosphorylated Foxo-3a resides in the nucleus, whereas Foxo-3a phosphorylation leads to its nuclear exclusion and inactivation. 11 Moreover, Foxo-1 and -3a represses angiogenesis by downregulating endothelial nitric oxide synthase. 12 Experimental evidences suggest that myocardial repair is, at least in part, dependent on c-kit receptor-expressing (c-kit pos ) progenitor cell populations. [13][14][15] Lineage negative Original received October 5, 2009; revision received February 19, 2010; accepted February 23, 2010. 13 Activation of the c-kit receptor is mediated by its ligand stem cell factor (SCF), a cytokine that exists in soluble or membraneassociated form. 16 The membrane-bound SCF isoform, which is predominant in vivo...

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