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(NPRs), which can either activate guanylyl cyclase (NPRA and NPRB) or inhibit adenylyl cyclase (NPRC) to modulate intracellular cGMP or cAMP, respectively. During cardiac development, ANP serves as an early maker of differentiating atrial and ventricular chamber myocardium. As development proceeds, expression of ANP persists in the atria but declines in the ventricles. Currently, it is not known whether ANP is secreted or the ANP-NPR signaling system plays any active role in the developing ventricles. Thus the primary aims of this study were to 1) examine biological activity of ANP signaling systems in embryonic ventricular myocardium, and 2) determine whether ANP signaling modulates proliferation/differentiation of undifferentiated cardiac progenitor cells (CPCs) and/or cardiomyocytes. Here, we provide evidence that ANP synthesized in embryonic day (E)11.5 ventricular myocytes is actively secreted and processed to its biologically active form. Notably, NPRA and NPRC were detected in E11.5 ventricles and exogenous ANP stimulated production of cGMP in ventricular cell cultures. Furthermore, we showed that exogenous ANP significantly decreased cell number and DNA synthesis of CPCs but not cardiomyocytes and this effect could be reversed by pretreatment with the NPRA receptorspecific inhibitor A71915. ANP treatment also led to a robust increase in nuclear p27 levels in CPCs compared with cardiomyocytes. Collectively, these data provide evidence that in the developing mammalian ventricles ANP plays a local paracrine role in regulating the balance between CPC proliferation and differentiation via NPRA/ cGMP-mediated signaling pathways. embryonic heart; ANP; natriuretic peptide receptors; gene expression; cardiac progenitor cells; cardiomyocytes; lineage tracking; knockin mice; cell proliferation and differentiation ATRIAL NATRIURETIC PEPTIDE (ANP) is a 28 amino acid peptide that is synthesized and stored primarily in secretory granules of atrial cardiomyocytes in the adult heart. Ligand binding of ANP to its cognate natriuretic peptide receptors (NPRs) can either activate guanylyl cyclase (NPRA and NPRB) or inhibit adenylyl cyclase (NPRC) to modulate intracellular cGMP or cAMP, respectively. The primary stimulus for ANP secretion from atrial cardiomyocytes is mechanical stretch of the atrial wall (15). In addition to mechanical stimuli, several vasoconstrictor peptides including endothelin-1 (ET-1) (36) and angiotensin II (9), as well as a variety of neurohormones, growth factors, and cytokines, have been shown to modulate natriuretic peptide secretion (10). Once in the circulation, ANP acts in a true endocrine fashion by stimulating NPRA receptors in the kidneys, adrenal cortex, and vasculature to regulate fluid homeostasis and maintain blood pressure via diuretic, natriuretic and vasorelaxant effects (29). In the ventricles of the adult heart, the levels of ANP protein are normally ϳ1,000-fold lower than in the atria and secretory granules are rarely observed (31).In contrast to the adult heart, developmental stud...

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Some boronated molecules have shown surprising physiological action; however, the mode of action of these compounds is not understood. Our hypothesis is that the boron moiety is attracted to Lewis base sites on an enzyme and the resulting interaction causes an inhibition of the physiological pathway. To study this problem, quantum mechanical calculations of boron−nitrogen bond dissociation energies for 12 molecules have been calculated and compared with physiological activities including anti-hyperlipidemic and anti-neoplastic behavior. Results of linear correlation analysis between bond dissociation energy and physiological action have shown evidence that our hypothesis has merit. Possible locations of enzyme inhibition by boronated compounds are inferred. In addition, structural and energetic features of boronated molecules, including intramolecular electrostatic interactions and Lewis acidity, are discussed.