Lethal ischemia due to intracoronary endothelin in pigs

Ezra, David; Goldstein, Robert E.; Czaja, J. F.; Feuerstein, Giora

doi:10.1152/ajpheart.1989.257.1.h339

Cited by 54 publications

(36 citation statements)

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“…Preproendothelin-1 has been more extensively studied and documented in vascular endothelial cells, as well as smooth muscle cells, heart, lung, kidney, brain, and skin (27)(28)(29). Increased endothelin expression has been reported in pulmonary hyper- tension (36), myocardial ischemia (37), and congestive heart failure (38). These are conditions associated with elevated elastase activity where it would be advantageous to assess the possible protective effects of very high levels of elafin expression.…”

Section: Discussionmentioning

confidence: 99%

Targeted overexpression of elafin protects mice against cardiac dysfunction and mortality following viral myocarditis

Zaidi¹,

Hui²,

Cheah³

et al. 1999

J. Clin. Invest.

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Serine elastases degrade elastin, stimulate vascular smooth muscle cell migration and proliferation, and are associated with myocardial damage. To evaluate the impact of elastase inhibition on cardiovascular development and disease, transgenic mice were created in which the mouse preproendothelin-1 promoter was used to target elafin overexpression to the cardiovascular system. To distinguish the transgene from endogenous elafin, constructs were made incorporating a FLAG sequence; the COOH-terminus FLAG-tagged elafin construct produced a stable, functionally active gene product and was used to create transgenic mice. Consistent with endothelin expression, abundant elafin mRNA was observed in transgenic F1 embryos (embryonic day 13.5) and in adult transgenic mice heart, trachea, aorta, kidney, lung, and skin, but not in liver, spleen, and intestine. Functional activity of the transgene was confirmed by heightened myocardial elastase inhibitory activity. No tissue abnormalities were detected by light microscopy or elastin content. However, injection of 10 plaque-forming units (PFU) of encephalomyocarditis virus resulted in death within 11 days in 10 out of 12 nontransgenic mice compared with one out of nine transgenic littermates. This reduced mortality was associated with better cardiac function and less myocardial inflammatory damage. Thus, elafin expression may confer a protective advantage in myocarditis and other inflammatory diseases.

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Section: Discussionmentioning

confidence: 99%

Targeted overexpression of elafin protects mice against cardiac dysfunction and mortality following viral myocarditis

Zaidi¹,

Hui²,

Cheah³

et al. 1999

J. Clin. Invest.

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“…ET-1 acts via two G protein-coupled receptors (ET A and ET B ), although the ET A receptor represents 90% of endothelin receptors in cardiomyocytes (Fareh et al, 1996;Sakai et al, 1996). ET-1 has been implicated in the pathophysiology of myocardial infarction and congestive heart failure (Ezra et al, 1989;Stewart et al, 1991;Grover et al, 1993), the latter role likely attributable to its potent hypertrophic actions, thus potentially contributing to the myocardial remodeling process (Yorikane et al, 1993). ET-1 and ET receptor expression can be increased by numerous Endothelin System in Cardiomyocyte Hypertrophy (Rubanyi and Polokoff, 1994).…”

Section: Discussionmentioning

confidence: 99%

Obligatory Role for Endogenous Endothelin in Mediating the Hypertrophic Effects of Phenylephrine and Angiotensin II in Neonatal Rat Ventricular Myocytes: Evidence for Two Distinct Mechanisms for Endothelin Regulation

Xia

Karmazyn²

2004

J Pharmacol Exp Ther

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Various G q protein-coupled receptor agonists such as the ␣ 1 adrenoceptor agonist phenylephrine, angiotensin II, and endothelin-1 are potent hypertrophic factors. There is evidence of potential cross talk between these agents, particularly in terms of endothelin-1 as playing a central role in mediating the actions of other hypertrophic factors. Using cultured rat neonatal ventricular myocytes, we assessed the potential cross talk between these factors and sought to examine the potential underlying mechanisms. Twenty-four-hour exposure to either agent produced significant hypertrophy as determined by cell size and molecular markers. Although the hypertrophic effects of phenylephrine and angiotensin II were expectedly prevented by ␣ 1 and AT 1 receptor antagonists, respectively, these effects were also blocked by the ET A receptor antagonist BQ123 [cyclo(D-Asp-Pro-D-Val-Leu-D-Trp)] but not by the ET B antagonist BQ788 (N-cis-2,6-dimethylpiperidinocarbonyl-L-␥-methylleucyl-D-1-methoxycarbonyltryptophanyl-D-norleucine). Both phenylephrine and angiotensin II significantly increased protein expression of both endothelin receptor subtypes. Both phenylephrine and angiotensin II produced significant activation of p38 as well as extracellular signal-regulated protein kinase and c-Jun NH 2 -terminal kinase, although this was unaffected by endothelin receptor blockade. Further studies revealed that the effects of phenylephrine and angiotensin II were mediated by stimulated endothelin-1 production occurring via two separate mechanisms: angiotensin II by increasing the levels of the endothelin-1 precursor prepro endothelin-1 and phenylephrine by upregulating endothelin-converting enzyme 1. Our results indicate that the endothelin-1 system plays an obligatory role in the hypertrophic response to both phenylephrine and angiotensin II in cultured myocytes through a mechanism independent of mitogenactivated protein kinase activation.

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“…Despite the vast knowledge about the role of ET-1 on cardiovascular physiology, its diastolic effects have only recently started to be uncovered. Accurate evidence was gathered in the setting of isolated muscle preparations and hemodynamic studies, inasmuch as in the intact heart it is difficult to differentiate between effects of ET-1 on intrinsic myocardial diastolic properties from those related to load changes [16,35] and coronary vasoconstriction [13,23]. Indeed, in the intact heart, effects of ET-1 on diastolic function might result from direct actions of the peptide and from indirect effects that are mainly the consequence of coronary and/or systemic vasoconstriction.…”

Section: Endothelinmentioning

confidence: 99%