Vol. 276, Issue 6, H2268-H2270, June 1999
EDITORIAL
Modulation of the adaptive response to myocardial ischemia by
coexisting disease
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ARTICLE |
THE LAST HALF OF THIS CENTURY has been distinguished by
vast progress in our understanding of physiological mechanisms that contribute to cellular, tissue, and organ protection against
ischemia. Perhaps most notable is the identification of the
endothelium-derived vasodilator nitric oxide (6) and ischemic
preconditioning (24) as powerful endogenous mechanisms producing
cardioprotection. Interestingly, nitric oxide and ischemic
preconditioning have been linked in the heart. Nitric oxide serves as a
key mediator of the "second window" or late phase of ischemic
preconditioning to reduce the extent of myocardial injury following
coronary artery occlusion and reperfusion (3, 33). In the May 1999 issue of AJP: Heart and Circulatory
Physiology, the ability of nitric oxide to limit
myocardial injury during ischemia was emphasized by the
findings of Jones et al. (12), who used endothelial cell nitric oxide
synthase (ecNOS)-deficient (knockout) mice and by Agulló et al.
(2), who used isolated rat hearts subjected to hypoxia and
reoxygenation. These studies indicate that nitric oxide and ultimately
increases in cGMP activity have a major impact on the extent of
myocardial injury occurring during ischemia or hypoxia.
Given the capacity of the heart to robustly respond to ischemic stimuli
by preconditioning and the ubiquitous nature of nitric oxide, it would
seem logical to assume that the myocardium should be readily adaptable
to such untoward events. Yet, worldwide, cardiovascular disease
accounts for 12 million deaths each year. The basis for the profound
morbidity and mortality associated with myocardial ischemia may
be related to the effects of coexisting disease on ischemia and
reperfusion injury. In fact, patients with coronary artery disease
commonly have concomitant hypertension and diabetes mellitus, two
diseases with a high impact on vascular endothelium. Clearly, future
research must be directed at the identification of mechanisms by which
coexisting disease interferes with endogenous cardioprotection, and
several key investigations reported here may provide a direction for
future work.
The role of nitric oxide to limit the extent of myocardial
ischemia and reperfusion injury has been suggested previously
(16, 26, 28), but the availability of pharmacological tools limited earlier investigations. In this May 1999 issue of the Journal, Jones et
al. (12) evaluated the role of nitric oxide to mitigate the degree of
myocardial infarction in mice genetically deficient in ecNOS.
Genetically altered mice demonstrated marked increases in infarct size
after coronary artery occlusion and reperfusion as compared with
wild-type mice. Increases in infarct size occurred concomitant with
enhanced expression of the endothelial cell adhesion molecule
P-selectin and with pronounced neutrophil infiltration into previously
ischemic tissue. These results emphasize the important effects of
nitric oxide synthase activity to reduce injury in the myocardium
occurring as a result of inflammatory responses mediated by neutrophils
and coronary vascular endothelium. Enhanced inflammatory responses to
ischemia and reperfusion via adhesion molecules have previously
been demonstrated in diabetic animals (29). The similar findings of
Jones et al. (12) in ecNOS-deficient mice support the contention that
impairment of nitric oxide may be partly responsible for maladaptation
to ischemia during diabetes mellitus.
Reminiscent of ischemic preconditioning, in the May issue of the
Journal, Agulló et al. (2) demonstrated that preanoxic administration of the nitric oxide precursor
L-arginine enhanced functional
recovery of myocardium and simultaneously increased cGMP release in
isolated rat hearts. Only pretreatment was effective, and
L-arginine was not
cardioprotective if administered solely during the anoxic or
reoxygenation periods. Furthermore, a selective antagonist of soluble
guanylate cyclase attenuated the benefit afforded by
L-arginine. Thus
nitric oxide and signal transduction through cGMP are shown again to
play critical roles in attenuating the extent of ischemic injury in
myocardium. The potential of nitric oxide to act as an effective
endogenous cardioprotective substance may be severely limited in
patients with coronary artery disease. Changes in nitric oxide
signaling pathways may prove to be a critical determinant of
insufficient myocardial adaptation to ischemia in hypertension,
atherosclerosis, diabetes mellitus, and heart failure, all disease
states associated with reduced availability of nitric oxide. For
example, it has long been recognized that the prognosis of patients
with diabetes mellitus is poor after acute myocardial infarction (1,
11, 17, 22), yet the mechanisms that account for this increased
morbidity and mortality are poorly understood. Diabetes, and even
hyperglycemia alone, cause vascular endothelial dysfunction as a result
of decreases in endothelial nitric oxide production and/or activity (7, 15, 19, 31, 37). Experimental acute hyperglycemia also abolishes the
protection afforded by ischemic preconditioning (14). Whereas some of
the deleterious effects of diabetes and hyperglycemia may be reversed
by administration of L-arginine (19, 26, 31), specific therapies to restore the efficacy of
cardioprotective pathways altered by these and other diseases remain
relatively unexplored.
Quenching of nitric oxide by the superoxide anion
(O
2) is increasingly being recognized
as an important pathophysiological consequence of many diseases,
including hypertension (34, 36), atherosclerosis (21, 32), and diabetes
(4, 30, 37). Provision of substrate (i.e.,
L-arginine) alone as a means to
restore nitric oxide activity may prove to be ineffective because of
interactions between nitric oxide and
O2 (9). The findings of Gupte et al.
(10) in the May issue of the Journal provide additional evidence of a
provocative link between cellular redox state and nitric oxide
activity. These investigators demonstrate that increased intracellular
concentrations of lactate cause a reduction in nitrovasodilator-induced
relaxation of pulmonary arteries and reduced activation of guanylate
cyclase when endogenous superoxide dismutase activity is
inhibited. Metabolism of lactate by the lactate
dehydrogenase enzyme increases intracellular NADH, a substrate for NADH
oxidase. The latter is an important source of
O2 in the pulmonary vasculature, and changes in cellular redox state lead to increases in
O2 production. Normally, increases in
O2 are mitigated by superoxide
dismutase; however, in the absence of sufficient SOD activity, nitric
oxide-mediated signaling is dramatically diminished. These results
suggest that, if endogenous SOD activity is decreased by disease,
alterations in the cellular redox state that occur during
ischemia may be met by an attenuated nitric oxide response.
Diminished nitric oxide action in such a case represents an example of
how coexisting disease may affect the adaptive response to an ischemic
event. This process is clearly demonstrated by the increases in oxidant
stress that occur during diabetes and hyperglycemia and contribute to
vascular endothelial dysfunction that may be reversible on
administration of free radical scavengers (4, 8, 18, 30).
It is unknown if treatment with antioxidants will ultimately enhance
the efficacy of endogenous cardioprotective mechanisms during disease
states associated with absolute or relative overproduction of
O2. This represents an important area
for future investigation.
Nitric oxide mediates adaptive responses to ischemia not only
through direct effects but also indirectly via the coronary vasculature. For example, nitric oxide has been shown to be responsible for tonic vasodilation of the coronary collateral circulation (5), and
diabetes (13, 25, 27) or atherosclerosis (21) impairs coronary
vasodilator responses to physiological and pharmacological stimuli.
Recently, Metais et al. (20) evaluated human coronary microvascular
responses to vascular endothelial growth factor in vitro. Vascular
endothelial growth factor caused dose-dependent relaxation of
microvessels obtained from patients without coronary artery disease.
The vasodilator responses were blocked by inhibition of nitric oxide
synthase and were absent in microvessels harvested from patients with
coronary artery disease. These results provide strong evidence that
coexisting disease may influence the adaptation to myocardial
ischemia. Such maladaptation to ischemia may also extend to an impairment of angiogenesis and vasculogenesis.
Angiogenesis was significantly impaired in the ischemic hindlimb of
ecNOS-deficient mice as compared with mice possessing the wild-type
gene (23) and was impaired by diabetes in a similar model
(35). Whereas coronary collateral development was not
specifically evaluated in these models, capillary density was decreased
in infarcted myocardium of diabetic patients (38). An important goal of
future research will be to determine whether alterations in nitric
oxide signaling or other mechanisms are responsible for insufficient coronary collateral development in some patients, whereas others may
adapt to chronic myocardial ischemia by new vessel growth. It
is clear that coexisting disease states markedly modify adaptive responses to myocardial ischemia. Determination of the
responsible mechanisms will present new challenges and may suggest new
treatment modalities, allowing the full potential of endogenous
cardioprotective mechanisms to be achieved.
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FOOTNOTES |
Address for reprint requests and other correspondence: J. R. Kersten, Medical College of Wisconsin, MEB-Room 462C, 8701 Watertown Plank Rd., Milwaukee, WI 53226 (E-mail:
jkersten{at}mcw.edu).
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REFERENCES |
1.
Abbud, Z. A.,
D. M. Shindler,
A. C. Wilson,
and
J. B. Kostis.
Effect of diabetes mellitus on short- and long-term mortality rates of patients with acute myocardial infarction: a statewide study.
Am. Heart J.
130:
51-58,
1995[Medline].
2.
Agulló, L.,
D. García-Dorado,
J. Inserte,
A. Paniagua,
P. Pyrhonen,
J. Llevadot,
and
J. Soler-Soler.
L-Arginine limits myocardial cell death secondary to hypoxia-reoxygenation by a cGMP-dependent mechanism.
Am. J. Physiol.
276 (Heart Circ. Physiol. 45):
H1574-H1580,
1999[Abstract/Free Full Text].
3.
Bolli, R.,
Z. A. Bhatti,
X. L. Tang,
Y. Qiu,
Q. Zhang,
Y. Guo,
and
A. K. Jadoon.
Evidence that late preconditioning against myocardial stunning in conscious rabbits is triggered by the generation of nitric oxide.
Circ. Res.
81:
42-52,
1997[Abstract/Free Full Text].
4.
Diederich, D.,
J. Skopec,
A. Diederich,
and
F. X. Dai.
Endothelial dysfunction in mesenteric resistance arteries of diabetic rats: role of free radicals.
Am. J. Physiol.
266 (Heart Circ. Physiol. 35):
H1153-H1161,
1994[Abstract/Free Full Text].
5.
Frank, M. W.,
K. R. Harris,
K. A. Ahlin,
and
F. J. Klocke.
Endothelium-derived relaxing factor (nitric oxide) has a tonic vasodilating action on coronary collateral vessels.
J. Am. Coll. Cardiol.
27:
658-663,
1996[Abstract].
6.
Furchgott, R. F.,
and
J. V. Zawadzki.
The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine.
Nature
288:
373-376,
1980[Medline].
7.
Gebremedhin, D.,
M. Z. Koltai,
G. Pogatsa,
K. Magyar,
and
P. Hadhazy.
Influence of experimental diabetes on the mechanical responses of canine coronary arteries: role of endothelium.
Cardiovasc. Res.
22:
537-544,
1988[Medline].
8.
Graier, W. F.,
S. Simecek,
B. G. Hoebel,
T. C. Wascher,
P. Dittrich,
and
G. M. Kostner.
Antioxidants prevent high-D-glucose-enhanced endothelial Ca2+/cGMP response by scavenging superoxide anions.
Eur. J. Pharmacol.
322:
113-122,
1997[Medline].
9.
Gryglewski, R. J.,
R. M. Palmer,
and
S. Moncada.
Superoxide anion is involved in the breakdown of endothelium-derived vascular relaxing factor.
Nature
320:
454-456,
1986[Medline].
10.
Gupte, S. A.,
T. Rupawalla,
K. M. Mohazzab-H,
and
M. S. Wolin.
Regulation of NO-elicited pulmonary artery relaxation and guanylate cyclase activation by NADH oxidase and SOD.
Am. J. Physiol.
276 (Heart Circ. Physiol. 45):
H1535-H1542,
1999[Abstract/Free Full Text].
11.
Jelesoff, N. E.,
M. Feinglos,
C. B. Granger,
and
R. M. Califf.
Outcomes of diabetic patients following acute myocardial infarction: a review of the major thrombolytic trials.
Coron. Artery Dis.
7:
732-743,
1996[Medline].
12.
Jones, S. P.,
W. G. Girod,
A. J. Palazzo,
D. N. Granger,
M. B. Grisham,
D. Jourd'heuil,
P. L. Huang,
and
D. J. Lefer.
Myocardial ischemia-reperfusion injury is exacerbated in absence of endothelial cell nitric oxide synthase.
Am. J. Physiol.
276 (Heart Circ. Physiol. 45):
H1567-H1573,
1999[Abstract/Free Full Text].
13.
Kersten, J. R.,
L. A. Brooks,
and
K. C. Dellsperger.
Impaired microvascular response to graded coronary occlusion in diabetic and hyperglycemic dogs.
Am. J. Physiol.
268 (Heart Circ. Physiol. 37):
H1667-H1674,
1995[Abstract/Free Full Text].
14.
Kersten, J. R.,
T. J. Schmeling,
K. G. Orth,
P. S. Pagel,
and
D. C. Warltier.
Acute hyperglycemia abolishes ischemic preconditioning in vivo.
Am. J. Physiol.
275 (Heart Circ. Physiol. 44):
H721-H725,
1998[Abstract/Free Full Text].
15.
Koltai, M. Z.,
P. Hadhazy,
I. Posa,
E. Kocsis,
G. Winkler,
P. Rosen,
and
G. Pogatsa.
Characteristics of coronary endothelial dysfunction in experimental diabetes.
Cardiovasc. Res.
34:
157-163,
1997[Medline].
16.
Lefer, D. J.,
K. Nakanishi,
W. E. Johnston,
and
J. Vinten-Johansen.
Antineutrophil and myocardial protecting actions of a novel nitric oxide donor after acute myocardial ischemia and reperfusion of dogs.
Circulation
88:
2337-2350,
1993[Abstract/Free Full Text].
17.
Malmberg, K.,
and
L. Ryden.
Myocardial infarction in patients with diabetes mellitus.
Eur. Heart J.
9:
259-264,
1988[Abstract/Free Full Text].
18.
Marfella, R.,
G. Verrazzo,
R. Acampora,
C. La Marca,
R. Giunta,
C. Lucarelli,
G. Paolisso,
A. Ceriello,
and
D. Giugliano.
Glutathione reverses systemic hemodynamic changes induced by acute hyperglycemia in healthy subjects.
Am. J. Physiol.
268 (Endocrinol. Metab. 31):
E1167-E1173,
1995[Abstract/Free Full Text].
19.
Matsunaga, T.,
K. Okumura,
H. Ishizaka,
R. Tsunoda,
S. Tayama,
T. Tabuchi,
and
H. Yasue.
Impairment of coronary blood flow regulation by endothelium-derived nitric oxide in dogs with alloxan-induced diabetes.
J. Cardiovasc. Pharmacol.
28:
60-67,
1996[Medline].
20.
Metais, C.,
J. Li,
J. Li,
M. Simons,
and
F. W. Sellke.
Effects of coronary artery disease on expression and microvascular response to VEGF.
Am. J. Physiol.
275 (Heart Circ. Physiol. 44):
H1411-H1418,
1998[Abstract/Free Full Text].
21.
Miller, F. J., Jr.,
D. D. Gutterman,
C. D. Rios,
D. D. Heistad,
and
B. L. Davidson.
Superoxide production in vascular smooth muscle contributes to oxidative stress and impaired relaxation in atherosclerosis.
Circ. Res.
82:
1298-1305,
1998[Abstract/Free Full Text].
22.
Muggeo, M.,
G. Verlato,
E. Bonora,
G. Zoppini,
M. Corbellini,
and
R. de Marco.
Long-term instability of fasting plasma glucose, a novel predictor of cardiovascular mortality in elderly patients with non-insulin-dependent diabetes mellitus: the Verona Diabetes Study.
Circulation
96:
1750-1754,
1997[Abstract/Free Full Text].
23.
Murohara, T.,
T. Asahara,
M. Silver,
C. Bauters,
H. Masuda,
C. Kalka,
M. Kearney,
D. Chen,
J. F. Symes,
M. C. Fishman,
P. L. Huang,
and
J. M. Isner.
Nitric oxide synthase modulates angiogenesis in response to tissue ischemia.
J. Clin. Invest.
101:
2567-2578,
1998[Medline].
24.
Murry, C. E.,
R. B. Jennings,
and
K. A. Reimer.
Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium.
Circulation
74:
1124-1136,
1986[Abstract/Free Full Text].
25.
Nahser, P. J., Jr.,
R. E. Brown,
H. Oskarsson,
M. D. Winniford,
and
J. D. Rossen.
Maximal coronary flow reserve and metabolic coronary vasodilation in patients with diabetes mellitus.
Circulation
91:
635-640,
1995[Abstract/Free Full Text].
26.
Nakanishi, K.,
J. Vinten-Johansen,
D. J. Lefer,
Z. Zhao,
W. C. Fowler III,
D. S. McGee,
and
W. E. Johnston.
Intracoronary L-arginine during reperfusion improves endothelial function and reduces infarct size.
Am. J. Physiol.
263 (Heart Circ. Physiol. 32):
H1650-H1658,
1992[Abstract/Free Full Text].
27.
Nitenberg, A.,
F. Paycha,
S. Ledoux,
R. Sachs,
J. R. Attali,
and
P. Valensi.
Coronary artery responses to physiological stimuli are improved by deferoxamine but not by L-arginine in non-insulin-dependent diabetic patients with angiographically normal coronary arteries and no other risk factors.
Circulation
97:
736-743,
1998[Abstract/Free Full Text].
28.
Pabla, R.,
A. J. Buda,
D. M. Flynn,
S. A. Blesse,
A. M. Shin,
M. J. Curtis,
and
D. J. Lefer.
Nitric oxide attenuates neutrophil-mediated myocardial contractile dysfunction after ischemia and reperfusion.
Circ. Res.
78:
65-72,
1996[Abstract/Free Full Text].
29.
Panés, J.,
I. Kurose,
M. D. Rodriguez-Vaca,
D. C. Anderson,
M. Miyasaka,
P. Tso,
and
D. N. Granger.
Diabetes exacerbates inflammatory responses to ischemia-reperfusion.
Circulation
93:
161-167,
1996[Abstract/Free Full Text].
30.
Pieper, G. M.,
and
G. J. Gross.
Oxygen free radicals abolish endothelium-dependent relaxation in diabetic rat aorta.
Am. J. Physiol.
255 (Heart Circ. Physiol. 24):
H825-H833,
1988[Abstract/Free Full Text].
31.
Pieper, G. M.,
and
B. A. Peltier.
Amelioration by L-arginine of a dysfunctional arginine/nitric oxide pathway in diabetic endothelium.
J. Cardiovasc. Pharmacol.
25:
397-403,
1995[Medline].
32.
Pritchard, K. A., Jr.,
L. Groszek,
D. M. Smalley,
W. C. Sessa,
M. Wu,
P. Villalon,
M. S. Wolin,
and
M. B. Stemerman.
Native low-density lipoprotein increases endothelial cell nitric oxide synthase generation of superoxide anion.
Circ. Res.
77:
510-518,
1995[Abstract/Free Full Text].
33.
Qiu, Y.,
A. Rizvi,
X. L. Tang,
S. Manchikalapudi,
H. Takano,
A. K. Jadoon,
W. J. Wu,
and
R. Bolli.
Nitric oxide triggers late preconditioning against myocardial infarction in conscious rabbits.
Am. J. Physiol.
273 (Heart Circ. Physiol. 42):
H2931-H2936,
1997.
34.
Rajagopalan, S.,
S. Kurz,
T. Munzel,
M. Tarpey,
B. A. Freeman,
K. K. Griendling,
and
D. G. Harrison.
Angiotensin II-mediated hypertension in the rat increases vascular superoxide production via membrane NADH/NADPH oxidase activation. Contribution to alterations of vasomotor tone.
J. Clin. Invest.
97:
1916-1923,
1996[Medline].
35.
Rivard, A.,
M. Silver,
J.-E. Fabre,
M. Magner,
M. Kearney,
and
J. M. Isner.
Diabetes impairs angiogenesis in limb ischemia.
Circulation
96:
I-175,
1997.
36.
Suzuki, H.,
A. Swei,
B. W. Zweifach,
and
G. W. Schmid-Schonbein.
In vivo evidence for microvascular oxidative stress in spontaneously hypertensive rats. Hydroethidine microfluorography.
Hypertension
25:
1083-1089,
1995[Abstract/Free Full Text].
37.
Tesfamariam, B.,
and
R. A. Cohen.
Free radicals mediate endothelial cell dysfunction caused by elevated glucose.
Am. J. Physiol.
263 (Heart Circ. Physiol. 32):
H321-H326,
1992[Abstract/Free Full Text].
38.
Yarom, R.,
H. Zirkin,
G. Stammler,
and
A. G. Rose.
Human coronary microvessels in diabetes and ischaemia. Morphometric study of autopsy material.
J. Pathol.
166:
265-270,
1992[Medline].
| | | | |
Judy R. Kersten,
David C. Warltier,
Departments of 1 Anesthesiology,
2 Pharmacology and Toxicology, and
3 Medicine (Division of
Cardiovascular Diseases), Medical College of Wisconsin, Milwaukee
53226; and 4 Zablocki Veterans
Affairs Medical Center, Milwaukee, Wisconsin 53295
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Am J Physiol Heart Circ Physiol 276(6):H2268-H2270
0002-9513/99 $5.00
Copyright © 1999 the American Physiological Society
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