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Isolation of Endocardial and Coronary Endothelial Cells from the Ventricular Free Wall of the Rat Heart
Published on: April 15, 2020
Microsomal prostaglandin E2 synthase-1 deletion leads to adverse left ventricular remodeling after myocardial
Norbert Degousee1, Shafie Fazel, Denis Angoulvant
1Division of Vascular Surgery, University of Toronto, Toronto, Ontario, Canada M5G-2C4.
Background:
Pharmacological inhibition of cyclooxygenase-2 increases the risk of myocardial infarction (MI) and stroke. Microsomal prostaglandin (PG) E(2) synthase-1 (mPGES-1), encoded by the Ptges gene, functions downstream from cyclooxygenase-2 in the inducible PGE(2) biosynthetic pathway. We caused acute MI in Ptges(+/+) and Ptges(-/-) mice to define the role of mPGES-1 in cardiac ischemic injury.
Methods And Results:
Twenty-eight days after MI, Ptges(-/-) mice develop more left ventricular (LV) dilation, have worse LV systolic and diastolic function, and have higher LV end-diastolic pressure than Ptges(+/+) mice but have similar pulmonary wet-to-dry weight ratios, cardiac mass, infarct size, and mortality. The length-to-width ratio of individual cardiomyocytes is significantly greater in Ptges(-/-) than Ptges(+/+) mice after MI, a finding consistent with eccentric cardiomyocyte hypertrophy in Ptges(-/-) mice. Expression of atrial natriuretic peptide, brain natriuretic peptide, and alpha- and beta-myosin heavy chain, markers of ventricular hypertrophy, is higher in the LV of Ptges(-/-) than Ptges(+/+) mice after MI. Ptges(+/+) mice express cyclooxygenase-2 and mPGES-1 protein in inflammatory cells adjacent to the infarct after MI but do not express these proteins in cardiomyocytes. Ptges(-/-) mice express cyclooxygenase-2 in inflammatory cells adjacent to the infarct and do not express mPGES-1 in any cells in the heart. Levels of PGE(2) but not PGD(2), thromboxane A(2), PGI(2), or PGF(2alpha) are higher in the infarct and LV remote from the infarct after MI in Ptges(+/+) than Ptges(-/-) mice.
Conclusions:
In Ptges(+/+) mice, mPGES-1 in inflammatory cells catalyzes PGE(2) biosynthesis in the LV after MI. Deletion of mPGES-1 leads to eccentric cardiac myocyte hypertrophy, LV dilation, and impaired LV contractile function after acute MI.
Insights
Microsomal prostaglandin E(2) synthase-1 (mPGES-1) deletion worsens cardiac function after myocardial infarction (MI). Loss of mPGES-1 causes eccentric cardiac myocyte hypertrophy and left ventricular dilation, impairing heart function post-MI.
Area of Science:
- Cardiovascular Research
- Molecular Biology
- Inflammation Research
Background:
- Pharmacological inhibition of cyclooxygenase-2 is linked to increased risk of myocardial infarction (MI) and stroke.
- Microsomal prostaglandin E(2) synthase-1 (mPGES-1), encoded by the Ptges gene, is a key enzyme in the inducible PGE(2) pathway downstream of cyclooxygenase-2.
Purpose of the Study:
- To investigate the role of mPGES-1 in cardiac ischemic injury.
- To define the function of mPGES-1 in the context of acute myocardial infarction (MI).
Main Methods:
- Induction of acute MI in wild-type (Ptges(+/+)) and mPGES-1 knockout (Ptges(-/-)) mice.
- Assessment of left ventricular (LV) structure and function 28 days post-MI.
- Analysis of cardiomyocyte size, ventricular hypertrophy markers, and prostaglandin levels.
Main Results:
- Ptges(-/-) mice exhibited increased LV dilation, impaired systolic and diastolic function, and higher LV end-diastolic pressure compared to Ptges(+/+) mice post-MI.
- Eccentric cardiomyocyte hypertrophy and elevated expression of hypertrophy markers were observed in Ptges(-/-) mice.
- PGE(2) levels were significantly lower in the infarct and LV of Ptges(-/-) mice compared to Ptges(+/+) mice after MI.
Conclusions:
- mPGES-1, primarily in inflammatory cells, catalyzes PGE(2) biosynthesis in the left ventricle following MI.
- Deletion of mPGES-1 results in eccentric cardiac myocyte hypertrophy, LV dilation, and impaired contractile function after acute MI.
