Sarah K. Jimenez

Fibroblast growth factor-2 and cardioprotection.

Boosting myocardial resistance to acute as well as chronic ischemic damage would ameliorate the detrimental effects of numerous cardiac pathologies and reduce the probability of transition to heart failure. Experimental cardiology has pointed to ischemic and pharmacological pre- as well as post-conditioning as potent acute cardioprotective manipulations. Additional exciting experimental strategies include the induction of true regenerative and/or angiogenic responses to the damaged heart, resulting in sustained structural and functional beneficial effects. Fibroblast growth factor-2 (FGF-2), an endogenous multifunctional protein with strong affinity for the extracellular matrix and basal lamina and well-documented paracrine, autocrine and intacellular modes of action, has been shown over the years to exert acute and direct pro-survival effects, irrespectively of whether it is administered before, during or after an ischemic insult to the heart. FGF-2 is also a potent angiogenic protein and a crucial agent for the proliferation, expansion, and survival of several cell types including those with stem cell properties. Human clinical trials have pointed to a good safety record for this protein. In this review, we will present a case for the low molecular weight isoform of fibroblast growth factor-2 (lo-FGF-2) as a very promising therapeutic agent to achieve powerful acute as well as sustained benefits for the heart, due to its cytoprotective and regenerative properties.

The Application of Genetic Mouse Models to Elucidate a Role for Fibroblast Growth Factor-2 in the Mammalian Cardiovascular System

Fibroblast growth factor (FGF)-2 is a polypeptide growth factor which plays multiple roles in the mammalian cardiovascular system, having direct proliferative, migratory and differentiation effects on cardiac myocytes, fibroblasts, smooth muscle and endothelial cells. To date, a number of genetic approaches in mice have been used to further our understanding of these roles and effects. The three main approaches used so far have been overexpression, gene disruption (“knockout”), and the use of a reporter gene for the study of transcriptional regulation in vivo. The application of genetic models offers the advantage of endogenous production, depletion or regulation as opposed to exogenously added growth factor or regulation studied ex vivo. The variety of approaches available has resulted in the publication of two overexpression models, four separate “knockout” models and one reporter gene system in transgenic mice. These models have been summarized in this review and will be discussed collectively in the context of the many roles for FGF-2 in the cardiovascular system, including development, cardioprotection, angiogenesis, blood pressure regulation, and hypertrophy. The reporter gene system will be highlighted in terms of the study of gene regulation in vivo. Finally, various means for fine-tuning transgenic systems will be considered with respect to the ability to control endogenous FGF-2 production more precisely.