Prostaglandin F2α Stimulates Hypertrophic Growth of Cultured Neonatal Rat Ventricular Myocytes

Abstract

During embryonic development the myocardium enlarges by the proliferation of cardiac myocytes. Shortly after birth, cardiac myocytes lose their capacity for mitogenesis, and further growth of the myocardium to meet the increasing hemodynamic demand of an elevated blood pressure and blood volume occurs by enlargement of existing muscle cells (hypertrophy). Similarly, the restoration of myocardial contractile performance lost to ischemia or viral infection is dependent on the recovery of injured myocytes and on the compensatory enlargement of agonist myocytes. Thus, an understanding of the controlling factors of myocardial protein synthesis and growth has implications for cardiac ontogeny, adaptation to chronic physiologic and pathophysiologic stimuli, and recovery from injury.Cardiac hypertrophy is produced by a variety of stimuli in culture and in vivo (1), including, but not limited to, mechanical stretch (2, 3), neurotransmitters (4, 5), and hormones (6, 7). As the biochemistry of myocardial growth is experimentally revealed, some common intracellular signaling pathways appear among primary stimuli. For example, stretch-induced cardiomyocyte hypertrophy is mediated, in part, by the local production of angiotensin II (8), and several hypertrophic stimuli, angiotensin II, norepinephrine, and endothelin-1, act through G q protein-coupled receptors (9 -11) and activate mitogen-activated protein kinases (12, 13). Direct evidence of G q involvement in cardiac growth was provided by microinjection of G q neutralizing antibodies to block the hypertrophic response of neonatal rat ventricular myocytes to the ␣ 1 -adrenergic agonist phenylephrine (9). Thus cardiac hypertrophy appears to be mediated, at least for several stimuli, by agonists of G q proteincoupled receptors.In addition to promoting myocardial growth, angiotensin II, norepinephrine, and endothelin-1 are vasoactive substances. Interestingly, Katz (14) speculated that angiotensin II evolved from a primitive growth factor and assumed additional regulatory roles in the cardiovascular system, such as stimulation of aldosterone production and smooth muscle contraction. It is conceivable that other vasoactive substances went through a similar evolutionary process, especially in consideration of the finding that Ca 2ϩ signaling is important for angiotensin II activation of mitogen-activated protein kinase in cardiac myocytes (13).Prostaglandin F 2␣ (PGF 2␣ ) 1 is a vasoactive substance that stimulates protein synthesis in skeletal and smooth muscle cells in culture (15,16). Moreover, PGF 2␣ regulates, in part, stretch-induced skeletal myoblast growth (16), and the effects of exogenous PGF 2␣ on vascular smooth muscle hypertrophy are most likely mediated by a PGF-specific receptor (15). As to the heart, PGF 2␣ was increased in the left ventricles of rabbits by acute pressure overload (17), and PG synthase inhibitors blocked cardiac growth induced by hypertension (18) and clenbuterol (19). These observations and others suggested that PGF 2␣ may play a role in the con...

Upregulation of orphan nuclear receptor Nur77 following PGF2α, Bimatoprost, and Butaprost treatments. Essential role of a protein kinase C pathway involved in EP2 receptor activated Nur77 gene transcription

“…Activation of FP receptors initiated by ligand binding triggers Gaq protein-coupled mechanisms involved Ca 2 þ signaling, IP 3 turnover, and activation of protein kinase C (Toh et al, 1995). PGF 2a has diverse physiological actions that include causing smooth muscle (SM) contraction (Horton & Poyser, 1976), stimulating DNA synthesis and cell proliferation, and cardiac myocyte hypertrophy (Adams et al, 1996). Importantly, PGF 2a analogs have been used clinically to reduce ocular hypertension (Woodward et al, 1993a).…”

G-proteins in growth and apoptosis: lessons from the heart

“…Thus probably this G-protein coupled receptor agonist contributes to the development of cardiac hypertrophy in vivo. PGF2a is an exceedingly e ective stimulus for cardiomyocyte hypertrophy in NRVMs (Adams et al, 1996;Lai et al, 1996). Notably, PGF2a is upregulated in the stressed myocardium (Lai et al, 1996) suggesting that it may also participate in the autocrine/paracrine growth signaling response that underlie hypertrophy in the challenged heart.…”

“…Gi (Sekiguchi et al, 1999) regulate the heterotrimeric G-protein Gq (see Table 1). Gq-coupled receptor agonists shown to induce hypertrophy in NRVM include norepinephrine (NE), angiotensin II (Ang II), endothelin-1 (ET-1), thrombin, lysophosphatidic acid (LPA) and prostaglandin F2a (PGF2a) (Simpson et al, 1982;Sadoshima and Izumo, 1993a;Ito et al, 1991;Glembotski et al, 1993;Goetzl et al, 2000;Adams et al, 1996). The activated alpha subunit of Gq directly stimulates phospholipase (PLC), catalyzing the hydrolysis of phosphatidylinositol bisphosphate (PIP 2 ).…”

PGF2α-associated vascular smooth muscle hypertrophy is ROS dependent and involves the activation of mTOR, p70S6k, and PTEN

“…PGF 2α has recently been shown to induce the hypertrophy of neonatal rat ventricular myocytes, vascular smooth muscle cells (VSMC), and skeletal muscle myocytes in vitro (4,(7)(8)(9)(10). Consistent with these data, chronic administration of the PGF 2α receptor analog, fluprostenol increases cardiac growth (heart weight-and ventricular weight-to-body weight ratios) in vivo (8), while inhibition of PG production diminishes the hypertrophic response induced by hypertension (11) and blocks the growth of skeletal myofibers in vivo (12,13).…”