Abstract 1218: Cardiac-specific Overexpression Of Human Phospholipase D2 Induces Myocardial Hypertrophy In Transgenic Mice
Myocardial phospholipase D (PLD), which is downstream to α1-adrenoceptors, endothelin ET-, and angiotensin II receptors, generates the second messengers phosphatidic acid and diacylglycerol which have been implicated in the pathogenesis of myocardial hypertrophy. The functional role of PLD activation in the heart could not be elucidated yet due to the lack of specific modulators of this signal transduction pathway. To study the significance of PLD for the development of myocardial hypertrophy, we have generated transgenic mice (TG) overexpressing human PLD2 under the control of the cardiospecific α-MHC promoter. In the four TG lines (hPLD2-TG) identified by PCR and Southern blot analysis ex-vivo PLD activity in the hearts of heterozygous 3-months old mice was 10- to 25-fold above wild-type (WT) littermates. Norepinephrine (2.5 mg/kg body weight/day) or vehicle was administered to hPLD2-TG and WT mice by osmotic minipump for 14 days. The hPLD2-TG mice displayed a cardiac hypertrophy phenotype as indicated by significantly increased heart weight/body weight (HW/BW) and left ventricular weight/body weight (LV/BW) ratios (HW/BW: hPLD2-TG 5.19±0.16 vs. WT 4.38±0.09; LV/BW: hPLD2-TG 3.44±0.08 vs. WT 2.96±0.07; p<0.001). Chronic norepinephrine infusion significantly increased HW/BW (4.92±0.15) and LV/BW (3.35±0.12) in WT but not hPLD2-TG mice (HW/BW 4.92±0.11; LV/BW 3.33±0.04). Myocardial PLD activity was significantly elevated in hPLD2-TG (14.37±2.00 PEtOH nmol/h/mg protein) vs. WT (0.65±0.08 PEtOH nmol/h/mg protein) but was not affected by chronic norepinephrine stimulation neither in hPLD2-TG nor in WT mice (18.18±0.44 vs. 0.67±0.06 PEtOH nmol/h/mg protein). In conclusion, transgenic mice with cardiac-specific overexpression of human PLD2 display a cardiac hypertrophy phenotype demonstrating first evidence for a functional role of the PLD signal transduction pathway in the development of myocardial hypertrophy in vivo. Norepinephrine stimulation does not further enhance myocardial hypertrophy in hPLD+/− mice and is not accompanied with increased PLD activity in nontransgenic mice indicating independent hypertrophic pathways of adrenergic stimulation and PLD signal transduction.