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Losartan decreases p42/44 MAPK signaling and preserves LZ+ MYPT1 expression.

Ararat E, Brozovich FV - PLoS ONE (2009)

Bottom Line: Heart failure is associated with impairment in nitric oxide (NO) mediated vasodilatation, which has been demonstrated to result from a reduction in the relative expression of the leucine zipper positive (LZ+) isoform of the myosin targeting subunit (MYPT1) of myosin light chain phosphatase.These data suggest that either reducing or blocking the effects of circulating angiotensin II, both decreases the activation of the p42/44 MAPK signaling cascade and preserves LZ+ MYPT1 expression.Thus, the ability of ACE-inhibitors and ARBs to modulate the vascular phenotype, to preserve normal flow mediated vasodilatation may explain the beneficial effects of these drugs compared to other forms of afterload reduction in the treatment of heart failure.

View Article: PubMed Central - PubMed

Affiliation: Division of Cardiovascular Diseases, Mayo Medical School, Rochester, Minnesota, United States of America.

ABSTRACT
Heart failure is associated with impairment in nitric oxide (NO) mediated vasodilatation, which has been demonstrated to result from a reduction in the relative expression of the leucine zipper positive (LZ+) isoform of the myosin targeting subunit (MYPT1) of myosin light chain phosphatase. Further, captopril preserves normal LZ+ MYPT1 expression, the sensitivity to cGMP-mediated vasodilatation and modulates the expression of genes in the p42/44 MAPK and p38 MAPK signaling cascades. This study tests whether angiotensin receptor blockade (ARB) with losartan decreases p42/44 MAPK or p38 MAPK signaling and preserves LZ+ MYPT1 expression in a rat infarct model of heart failure. In aortic smooth muscle, p42/44 MAPK activation increases and LZ+ MYPT1 expression falls after LAD ligation. Losartan treatment decreases the activation of p42/44 MAPK to the uninfarcted control level and preserves normal LZ+ MYPT1 expression. The expression and activation of p38 MAPK, however, is low and does not change following LAD ligation or with losartan therapy. These data suggest that either reducing or blocking the effects of circulating angiotensin II, both decreases the activation of the p42/44 MAPK signaling cascade and preserves LZ+ MYPT1 expression. Thus, the ability of ACE-inhibitors and ARBs to modulate the vascular phenotype, to preserve normal flow mediated vasodilatation may explain the beneficial effects of these drugs compared to other forms of afterload reduction in the treatment of heart failure.

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Left ventricular function is reduced in rats following LAD ligation.Bar graph for LVEF (mean±SEM) in uninfarcted, control rats (n = 9), as well as rats 4 weeks following LAD ligation treated with vehicle (CHF, n = 12) or losartan (CHF+losaratan, n = 9). The * indicates a significant difference (p<0.05) compared to control.
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pone-0005144-g001: Left ventricular function is reduced in rats following LAD ligation.Bar graph for LVEF (mean±SEM) in uninfarcted, control rats (n = 9), as well as rats 4 weeks following LAD ligation treated with vehicle (CHF, n = 12) or losartan (CHF+losaratan, n = 9). The * indicates a significant difference (p<0.05) compared to control.

Mentions: The uninfarcted control rats had normal cardiac function with LVEF averaging 71±1% (n = 9). Following LAD ligation, left ventricular function was significantly reduced with an LVEF of 43±1% (n = 12, p<0.05, Fig 1). Losartan therapy, following LAD ligation, did not improve LVEF compared to vehicle treatment (43±3%, n = 9). Compared to vehicle treatment post infarction, the heart rate was significantly higher in the losartan treated rats (304±6 bpm vs 328±8 bpm, p<0.05). Post LAD ligation LVESD (0.15±0.01 cm vs 0.17±0.02 cm) and LVEDD (0.82±0.05 cm vs 0.86±0.04 cm) were slightly larger in the losartan compared to vehicle therapy group, but these differences were not significant (p>0.05).


Losartan decreases p42/44 MAPK signaling and preserves LZ+ MYPT1 expression.

Ararat E, Brozovich FV - PLoS ONE (2009)

Left ventricular function is reduced in rats following LAD ligation.Bar graph for LVEF (mean±SEM) in uninfarcted, control rats (n = 9), as well as rats 4 weeks following LAD ligation treated with vehicle (CHF, n = 12) or losartan (CHF+losaratan, n = 9). The * indicates a significant difference (p<0.05) compared to control.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2663051&req=5

pone-0005144-g001: Left ventricular function is reduced in rats following LAD ligation.Bar graph for LVEF (mean±SEM) in uninfarcted, control rats (n = 9), as well as rats 4 weeks following LAD ligation treated with vehicle (CHF, n = 12) or losartan (CHF+losaratan, n = 9). The * indicates a significant difference (p<0.05) compared to control.
Mentions: The uninfarcted control rats had normal cardiac function with LVEF averaging 71±1% (n = 9). Following LAD ligation, left ventricular function was significantly reduced with an LVEF of 43±1% (n = 12, p<0.05, Fig 1). Losartan therapy, following LAD ligation, did not improve LVEF compared to vehicle treatment (43±3%, n = 9). Compared to vehicle treatment post infarction, the heart rate was significantly higher in the losartan treated rats (304±6 bpm vs 328±8 bpm, p<0.05). Post LAD ligation LVESD (0.15±0.01 cm vs 0.17±0.02 cm) and LVEDD (0.82±0.05 cm vs 0.86±0.04 cm) were slightly larger in the losartan compared to vehicle therapy group, but these differences were not significant (p>0.05).

Bottom Line: Heart failure is associated with impairment in nitric oxide (NO) mediated vasodilatation, which has been demonstrated to result from a reduction in the relative expression of the leucine zipper positive (LZ+) isoform of the myosin targeting subunit (MYPT1) of myosin light chain phosphatase.These data suggest that either reducing or blocking the effects of circulating angiotensin II, both decreases the activation of the p42/44 MAPK signaling cascade and preserves LZ+ MYPT1 expression.Thus, the ability of ACE-inhibitors and ARBs to modulate the vascular phenotype, to preserve normal flow mediated vasodilatation may explain the beneficial effects of these drugs compared to other forms of afterload reduction in the treatment of heart failure.

View Article: PubMed Central - PubMed

Affiliation: Division of Cardiovascular Diseases, Mayo Medical School, Rochester, Minnesota, United States of America.

ABSTRACT
Heart failure is associated with impairment in nitric oxide (NO) mediated vasodilatation, which has been demonstrated to result from a reduction in the relative expression of the leucine zipper positive (LZ+) isoform of the myosin targeting subunit (MYPT1) of myosin light chain phosphatase. Further, captopril preserves normal LZ+ MYPT1 expression, the sensitivity to cGMP-mediated vasodilatation and modulates the expression of genes in the p42/44 MAPK and p38 MAPK signaling cascades. This study tests whether angiotensin receptor blockade (ARB) with losartan decreases p42/44 MAPK or p38 MAPK signaling and preserves LZ+ MYPT1 expression in a rat infarct model of heart failure. In aortic smooth muscle, p42/44 MAPK activation increases and LZ+ MYPT1 expression falls after LAD ligation. Losartan treatment decreases the activation of p42/44 MAPK to the uninfarcted control level and preserves normal LZ+ MYPT1 expression. The expression and activation of p38 MAPK, however, is low and does not change following LAD ligation or with losartan therapy. These data suggest that either reducing or blocking the effects of circulating angiotensin II, both decreases the activation of the p42/44 MAPK signaling cascade and preserves LZ+ MYPT1 expression. Thus, the ability of ACE-inhibitors and ARBs to modulate the vascular phenotype, to preserve normal flow mediated vasodilatation may explain the beneficial effects of these drugs compared to other forms of afterload reduction in the treatment of heart failure.

Show MeSH
Related in: MedlinePlus