Inhibition of phenylephrine‐induced cardiac hypertrophy by docosahexaenoic acid

Abstract

Many of the cardiovascular benefits of fish oil result from the antiarrhythmic actions of the n-3 polyunsaturated lipids docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). The beneficial effects of DHA/EPA in patients with coronary artery disease and myocardial infarction may also result from modulation of the myocardial hypertrophic response. Hypertrophy was assessed in neonatal cardiomyocytes exposed to phenylephrine (PE) by measuring cell surface area, total protein synthesis ((14)C leucine incorporation), and the organization of sarcomeric alpha-actinin and by monitoring expression of atrial natriuretic factor (ANF). We report that PE induced a twofold increase in cell surface area and protein synthesis in cardiomyocytes. The hypertrophied cardiomyocytes also exhibited increased expression of ANF in perinuclear regions and organization of sarcomeric alpha-actinin into classical z-bands. Treatment of cardiomyocytes with 5 microM DHA effectively prevented PE-induced hypertrophy as shown by inhibition of surface area expansion and protein synthesis, inhibition of ANF expression, and prevention of alpha-actinin organization into z-bands. DHA treatment prevented PE-induced activation of Ras and Raf-1 kinase. The upstream inhibition of Ras --> Raf-1 effectively prevented translocation and nuclear localization of phosphorylated extracellularly regulated kinase 1 and 2 (Erk1/2). These effects consequently led to inhibition of nuclear translocation, and hence, activation of the downstream signaling enzyme p90 ribosomal S6 kinase (p90(rsk)). These results indicate that PE-induced cardiac hypertrophy can be minimized by DHA. Our results suggest that inhibition of Ras --> Raf-1 --> Erk1/2 --> p90(rsk) --> hypertrophy is one possible pathway by which DHA can inhibit cardiac hypertrophy. In vivo studies are needed to confirm these in vitro effects of DHA.

Copper reverses cardiomyocyte hypertrophy through vascular endothelial growth factor-mediated reduction in the cell size

“…Cell hypertrophy was induced by phenylephrine (PE, Sigma-Aldrich) at a final concentration of 100 μM for 48 h in serum-free media, following a procedure published previously [9]. At the end of the 48 h incubation, Cu in the form of copper sulfate was added directly to the cultures at a final concentration of 5 μM Cu element for additional 24 h incubation.…”

Potential impact of carbohydrate and fat intake on pathological left ventricular hypertrophy

“…Dietary fish oils can prevent LVH in transgenic mice with a carnitine transporter mutation, which was attributed to modified diacylglycerol composition and resultant inhibition of PKC activation [190]. Siddiqui et al demonstrated that n-3 polyunsaturated lipid docosahexaenoic acid (DHA) prevents cardiac hypertrophy by inhibition of the Ras-Raf1-Erk1/2-p90 rsk signaling pathway in a phenylephrine-induced hypertrophy model [191]. The role of PUFAs on lipid signaling via the PPAR system in cardiomyocytes remains to be clarified.…”

Dietary fish oil is antihypertrophic but does not enhance postischemic myocardial function in female mice

“…Takahashi et al (45) observed that dietary FO prevented the membrane translocation of several cytosolic protein kinase C isozymes and suggested that this may be the mechanism for the hypertrophy suppression in the JVS mice. In vitro studies in isolated neonatal rat cardiac myocytes (sex of rats not reported) have demonstrated that DHA and EPA inhibit the growth response (i.e., protein synthesis) induced by phenylephrine and endothelin-1 stimulation via the Ras/Raf/Erk1/2 and JNK signaling pathways (41,42). In the present study, the growth reduction effect of FO diet was observed without a prior hemodynamic loading stimulus and therefore likely reflects a direct modulation of intrinsic myocardial trophic maintenance signaling.…”