Captopril prevents myosin light chain phosphatase isoform switching to preserve normal cGMP-mediated vasodilatation

Chen, Frank C.; Ogut, Ozgur; Rhee, Albert Y.; Hoit, Brian D.; Brozovich, Frank V.

doi:10.1016/j.yjmcc.2006.05.018

Cited by 27 publications

(54 citation statements)

References 44 publications

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“…Consistent with our previously study [10], fractional shortening decreased from 60% at baseline in uninfarcted rats to 30% in rats after left anterior descending coronary artery ligation. Captopril attenuated the fall in left ventricular function; fractional shortening was 45%.…”

Section: Methodssupporting

confidence: 93%

“…As previously described [10, 11], using a well-studied surgical infarct model of CHF and a protocol approved by the Institutional Animal Care and Use Committee, adult male Sprague-Dawley rats (Harlan, Ind., USA) weighing 350–400 g were anesthetized by induction with vaporized isoflurane (3%/volume mixture) and subsequently intubated via direct laryngoscopy. After intubation, the animals were ventilated continuously (room air with 1.5%/volume mixture isoflurane) along with perfused isoflurane mixture using the small animal ventilator (model 683, Harvard).…”

Section: Methodsmentioning

confidence: 99%

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Gene Expression Profiles of Vascular Smooth Muscle Show Differential Expression of Mitogen-Activated Protein Kinase Pathways during Captopril Therapy of Heart Failure

Chen

Brozovich²

2008

J Vasc Res

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Congestive heart failure (CHF) is characterized by increased vascular tone and an impairment in nitric-oxide-mediated vasodilatation. We have demonstrated that the blunted response to nitric oxide is due, in part, to a reduction in the leucine-zipper-positive isoform of the myosin-targeting subunit (MYPT1) of myosin light-chain phosphatase. Additionally, we have shown that angiotensin-converting enzyme inhibition, but not afterload reduction with prazosin, preserves leucine-zipper-positive MYPT1 isoform expression in vascular smooth muscle cells and normalizes the sensitivity to cGMP-mediated vasodilatation. We therefore hypothesized that in CHF, growth regulators and cytokines downstream of the angiotensin II receptor are involved in modulating gene expression in vascular tissue. Rats were divided into control and captopril-treated groups following left coronary artery ligation. Gene expression profiles in the aorta and portal vein at baseline and 2 and 4 weeks after myocardial infarction (MI) were analyzed using microarray technology and quantitative real-time PCR. After MI, microarray analysis revealed differential mRNA expression of 21 genes in the aorta of captopril-treated rats 2 and 4 weeks after surgery when compared to gene expression profiles at baseline and without captopril therapy. Real-time PCR demonstrated that captopril suppressed the expression of protein kinases in the angiotensin-II-mediated mitogen-activated protein kinase signaling pathway, including Taok1 and Raf1. These data suggest that in CHF, captopril therapy modulates gene expression in vascular smooth muscle, and some of the beneficial effects of ACE inhibition may be due to differential gene expression in the vasculature.

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Section: Methodssupporting

confidence: 93%

Section: Methodsmentioning

confidence: 99%

Gene Expression Profiles of Vascular Smooth Muscle Show Differential Expression of Mitogen-Activated Protein Kinase Pathways during Captopril Therapy of Heart Failure

Chen

Brozovich²

2008

J Vasc Res

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“…If this is true, a reduced PKG-mediated activation of this unknown phosphatase in CH may diminish cGMP-induced inhibition of Thr696 phosphorylation. Alternatively, downregulation of the expression of the LZ of MYPT1 may reduce PKG-mediated inhibition of Thr696 phosphorylation (6,24,35). Studies show that the MYPT1 LZ may be required for PKG action on MYPT1 (18,41) and that MYPT1 LZ expression is downregulated under some pathophysiological conditions (6,24,35).…”

Section: Discussionmentioning

confidence: 99%

Preservation of cGMP-induced relaxation of pulmonary veins of fetal lambs exposed to chronic high altitude hypoxia: role of PKG and Rho kinase

Gao¹,

Portugal²,

Liu³

et al. 2008

American Journal of Physiology-Lung Cellular and Molecular Phys

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The roles of Rho kinase (ROCK) and cGMP-dependent protein kinase (PKG) in cGMP-mediated relaxation of fetal pulmonary veins exposed to chronic hypoxia (CH) were investigated. Fourth generation pulmonary veins were dissected from near-term fetuses ( approximately 140 days of gestation) delivered from ewes exposed to chronic high altitude hypoxia for approximately 110 days (CH) and from control ewes. After constriction with endothelin-1, 8-bromoguanosine 3',5'-cyclic monophosphate (8-Br-cGMP) caused a similar relaxation of both control and CH vessels. Rp-8-Br-PET-cGMPS (a PKG inhibitor) inhibited whereas Y-27632 (a ROCK inhibitor) augmented relaxation of control veins to 8-Br-cGMP. These effects were significantly diminished in CH veins. PKG protein expression and activity were greater whereas ROCK protein expression and activity were less in CH vessels compared with controls. Phosphorylation of threonine 696 (ROCK substrate) and serine 695 (PKG substrate) of the regulatory myosin phosphatase targeting subunit MYPT1 of myosin light chain (MLC) phosphatase was stimulated to a lesser extent in CH than in control veins by endothelin-1 (ROCK stimulant) and 8-Br-cGMP (PKG stimulant), respectively. The phosphorylation and dephosphorylation of MLC caused by endothelin-1 and 8-Br-cGMP, respectively, were less in CH veins than in controls. These results suggest that CH in utero upregulates PKG activity but attenuates PKG action in fetal pulmonary veins. These effects are offset by the diminished ROCK action on MYPT1 and MLC and thus lead to an unaltered response to cGMP.

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“…9 MYPT1, in turn, exists as several spliced variants in smooth muscle which undergo significant changes in expression with differentiation, different types of SMC, and in pathophysiological settings. 10,11 One variant in which a 31 nt exon is spliced into the sequence creates a stop codon that results in the shorter isoform being expressed. The "spliced out" isoform does not contain the 5Ј-upstream stop codon and results in a longer form being expressed.…”

mentioning

confidence: 99%

Myosin Phosphatase Regulatory Pathways

Lincoln

2007

Circulation Research

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Captopril prevents myosin light chain phosphatase isoform switching to preserve normal cGMP-mediated vasodilatation

Cited by 27 publications

References 44 publications

Gene Expression Profiles of Vascular Smooth Muscle Show Differential Expression of Mitogen-Activated Protein Kinase Pathways during Captopril Therapy of Heart Failure

Gene Expression Profiles of Vascular Smooth Muscle Show Differential Expression of Mitogen-Activated Protein Kinase Pathways during Captopril Therapy of Heart Failure

Preservation of cGMP-induced relaxation of pulmonary veins of fetal lambs exposed to chronic high altitude hypoxia: role of PKG and Rho kinase

Myosin Phosphatase Regulatory Pathways

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