Fibroblast growth factor-2-induced cardioprotection against myocardial infarction occurs via the interplay between nitric oxide, protein kinase signaling, and ATP-sensitive potassium channels

Abstract

Fibroblast growth factor-2 (FGF2) protects the heart from ischemia–reperfusion (I-R) injury via a vast network of protein kinases. In the heart, downstream effectors of these FGF2-triggered signals have not yet been identified. It is hypothesized that nitric oxide (NO) signaling and ATP-sensitive potassium (K_ATP) channel activity are key effectors of protein kinases activated by FGF2-mediated cardioprotection. Hearts with a cardiac-specific overexpression of FGF2 (FGF2 Tg) were subjected to I-R injury in the absence or the presence of selective inhibitors of NO synthase (NOS) isoforms or sarcolemmal (sarcK_ATP) and mitochondrial (mitoK_ATP) K_ATP channels. Multiple NOS isoforms are necessary for FGF2-mediated cardioprotection, and nitrite levels are significantly reduced in FGF2 Tg hearts upon inhibition of protein kinase C or mitogen-activated protein kinases. Likewise, sarcK_ATP and mitoK_ATP channels are important for cardioprotection elicited by endogenous FGF2. These findings suggest that FGF2-induced cardioprotection occurs via protein kinase-NOS pathways as well as K_ATP channel activity.

Keywords::

• Growth factor
• nitric oxide synthase
• extracellular signal regulated kinase (ERK)
• p38
• PKC
• transgenic mouse
• ischemia–reperfusion

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Correction to: Fibroblast growth factor-2-induced cardioprotection against myocardial infarction occurs via the interplay between nitric oxide, protein kinase signaling, and ATP-sensitive potassium channels

Acknowledgments

This work was supported by grants from the American Heart Association (SDG 23004N), the Pharmaceutical Research and Manufacturers of America (Research Starter Grant), NIH/NHLBI R01 (HL075633) to J. Schultz, an Undergraduate Student Summer Fellowship from the American Heart Association, Ohio Valley Association to D. Porter, and a NIH Training Grant (T35 DK060444) Medical Student Summer Fellowship to G. Carpenter. The authors gratefully acknowledge Dr Heinz Gögelein and Sanofi-Aventis for the gift of HMR1098. The authors would like to acknowledge M. Bender and A. Whitaker for their excellent animal husbandry, G. Newman for assistance with the isolated heart apparatus and I-R studies, David Palacios for assistance with the I-R+K_ATP channel inhibition studies, Laura Moon for assistance with measurement of nitrite levels, and N. Vatamaniuc for assistance with cardiac function data analysis.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.