Eduardo Guarda

Regulation of collagen degradation in the rat myocardium after infarction

Fibrillar collagens, essential for maintaining the structural integrity of the myocardium, are degraded by matrix metalloproteinase (MMP-1). In other tissues collagenolysis is an important component of wound healing. Here we examined collagen degradation in the myocardium after infarction. Collagenase activity, measured by zymography, and expression of matrix metalloproteinase (MMP-1) and tissue inhibitor of metalloproteinase (TIMP) mRNA, detected by Northern blotting and in situ hybridization, in the rat heart 6 h to 28 days after left coronary artery ligation were studied. Sham-operated rats served as controls. Infarcted left ventricle was compared to non-infarcted right ventricle and interventricular septum and to sham-operated tissues. We found a transient increase in collagenase activity in the infarcted left ventricle, which began at day 2 (4.5-fold increase compared to controls), peaked at day seven (6.5-fold increase) and declined thereafter, together with a concomitant increase and contribution in collagenolytic activity of gelatinases (MMP-2 and MMP-9). An increase in collagenase mRNA was not seen until day 7 and only in the infarcted ventricle, while changes in MMP-1 activity or mRNA expression were not observed at remote sites or in sham-operated controls. Transcription of TIMP mRNA was observed at 6 h (two-fold increase) in the infarcted ventricle, peaked on day two after MI (eight-fold increase) and slowly decreased thereafter. No change in TIMP mRNA expression was observed at remote sites or in sham-operated controls. Cells responsible for transcription of MMP-1 and TIMP mRNA were fibroblast-like cells, not inflammatory or endothelial cells. At the site of infarction post-translational activation of latent collagenase (MMP-1) plays a greater role in the wound healing response than transcription of collagenase mRNA. Collagenase mRNA is synthesized when the latent extracellular pool of MMP-1 is reduced through the activation of latent collagenases and gelatinases. TIMP mRNA synthesis is regulated by the activation of MMPs with the balance between collagenase activation and TIMP inhibition determining the amount of collagenolysis in infarcted tissue.

Myocardial fibrosis: role of angiotensin II and aldosterone

In this report we review the replacement (i.e., scarring) and reactive (i.e., perivascular and interstitial fibrosis) fibrous tissue responses found in the myocardium in response to effector hormones of the renin-angiotensin-aldosterone system. Experimental data are presented to indicate: a) endogenous or exogenous elevations in plasma angiotensin II are associated with acute cardiac myocyte necrosis and subsequent microscopic scarring; b) chronic elevations in plasma aldosterone (ALDO), relative to Na+ intake, are associated with a perivascular and interstitial fibrosis of the coronary and systemic circulations and are also seen in response to chronic administration of the mineralocorticoid hormone deoxycorticosterone (DOC); and c) chronic mineralocorticoid excess, due to ALDO or DOC, is associated with enhanced urinary K+ excretion, cardiac myocyte necrosis and scarring. Pharmacologic agents which interfere with these effector hormones (e.g., ACE inhibition and ALDO receptor antagonism) protect the myocardium against this pathologic structural remodeling created by the reactive and replacement (reparative) fibrosis. Evidence is also presented to indicate that chronic ACE inhibition is associated with a regression in reactive myocardial fibrosis. Based on these experimental findings we would suggest that clinical trials are indicated to address the prevention and regression of myocardial fibrosis--an important determinant of pathologic structural remodeling and abnormal myocardial stiffness.

Pathologic Hypertrophy With Fibrosis: The Structural Basis for Myocardial Failure

The major risk factor associated with the appearance of adverse cardiovascular events and outcome attributable to cardiovascular disease is left ventricular hypertrophy (LVH). Why this should be so resides not in the increase in myocardial mass per se, but in the disruption of myocardial structure. An abnormal accumulation of fibrillar collagen within the adventitia of intramyocardial coronary arteries and neighboring interstitial spaces represents such a distortion in structure. Furthermore, this fibrosis disrupts the electrical and mechanical behavior of the hypertrophied myocardium. Mechanisms responsible for fibrillar collagen accumulation have been examined in intact animals and cultured cardiac fibroblasts. In vivo studies indicate that myocardial fibrosis is associated with the presence of chronic mineralocorticoid excess, relative to sodium intake and excretion, not hemodynamic workload. Accordingly, fibrosis can appear in both the hypertensive, hypertrophied and nonhypertensive, nonhypertrophied ventricles. In both primary and secondary hyperaldosteronism it was possible to prevent myocardial fibrosis with an aldosterone receptor antagonist, while in unilateral renal ischemia angiotensin converting enzyme (ACE) inhibition was similarly cardioprotective. A regression in fibrous tissue and normalization of diastolic stiffness has also been possible using ACE inhibition, bringing forward the concept of cardioreparation and the notion that heart failure due to fibrosis may be reversible. In vitro studies indicate that effector hormones of the renin-angiotensin-aldosterone system stimulate fibroblast collagen synthesis. Aldosterone, in pathophysiologic concentrations, and angiotensin II, in much larger concentrations, each enhance collagen synthesis without altering the mitogenic potential of these cells. Thus, elevations in circulating aldosterone and angiotensin II, relative to sodium intake, have the potential to not only alter sodium homeostasis and vascular tonicity, but also the structure of cardiovascular tissue. Thus, myocardial fibrosis represents a structural basis for pathologic hypertrophy and ultimately accounts for the appearance of adverse cardiovascular events and outcomes.

Effects of Angiotensin II on Canine and Porcine Coronary Epicardial and Resistance Arteries

Coronary resistance arteriolar diameter importantly regulates myocardial blood flow, and is influenced by circulating neurohumoral agents. Angiotensin II (A-II) is a circulating polypeptide that is chronically elevated in heart failure and serves as a potent peripheral vasoconstrictor agent. However, its effects on isolated coronary resistance arterioles is relatively unknown. We compared the vasomotor effects of A-II on coronary epicardial and resistance arterioles in vitro from both the canine and porcine heart in order to determine the effects of A-II in different vascular beds and species. Epicardial rings were studied under isometric recording conditions, while resistance arterioles (50-150 microns) were studied in vitro using a video imaging system to record diameter. A-II, whether applied to passively distended or preconstricted porcine resistance arterioles, did not cause vasoconstriction when applied as a bolus or as cumulative doses. In preconstricted canine resistance arterioles, A-II elicited dose-dependent vasodilation (EC50 = 0.2 nM). In passively distended canine arterioles, high concentrations of A-II (0.1 microM) applied as a bolus elicited transient vasoconstriction in 28% of the vessels studied. In large epicardial rings, A-II was a weak vasoconstrictor, with greater potency in canine arteries compared to porcine arteries. In canine arteries, vasoconstriction to A-II was augmented after incubation with indomethacin. In contrast to the findings in canine arteries, the A-II vasoconstrictor response in porcine coronary arteries was decreased after incubation with indomethacin or removal of the endothelium. Thus, A-II elicits the release of a vasodilator prostanoid in epicardial canine coronary arteries and a vasoconstrictor prostanoid in porcine vessels which modulate the vasomotor action of A-II.(ABSTRACT TRUNCATED AT 250 WORDS)

Myokardfibrose: Die Rolle von Angiotensin II und Aldosteron

In diesem Bericht geben wir einen Uberblick uber die Ersatz- (d. h. Bildung von Narbengewebe) und die reaktiven fibrosen Gewebsveranderungen (d. h. perivaskulare und interstitielle Fibrose), die man im Myokard als Reaktion auf Effektorhormone des Renin-Angiotensin-Aldosteron-Systems findet. Es werden experimentelle Daten vorgestellt um zu zeigen, das a) endogene oder exogene Erhohungen von Angiotensin II im Plasma mit einer akuten Nekrose kardialer Myozyten einhergehen und das es daraufhin zu einer mikroskopisch nachweisbaren Narbenbildung kommt; b) chronische Erhohungen des Aldosterons (ALDO) im Plasma, die mit der Na+-Zufuhr zusammenhangen, mit einer perivaskularen und interstitiellen Fibrose des koronaren und des systematischen Kreislaufs einhergehen, und das man diese Erhohungen auch als Reaktion auf eine chronische Verabreichung des Mineralcorticoidhormons Deoxycorticosteron (DOC) beobachten kann; und c) ein chronischer Mineralcorticoiduberschus aufgrund von ALDO oder DOC mit einer vermehrten K+-Ausscheidung im Urin zusammenhangt, mit einer Nekrose kardialer Myozyten und mit einer Narbenbildung. Pharmakologische Substanzen, die mit diesen Effektorhormonen interferieren (d. h. ACE-Inhibition und ALDO-Rezeptor-Antagonismus) schutzen das Myokard vor diesem pathologischen strukturellen Umbau, der von der reaktiven und Ersatz- (reparativen) Fibrose hervorgerufen wird. Es werden auch Anhaltspunkte vorgestellt, die darauf hinweisen, das eine chronische ACE-Inhibition mit einer Regression der reaktiven Myokardfibrose einhergeht. Aufgrund dieser experimentellen Befunde mochten wir vorschlagen, das klinische Untersuchungen angezeigt sind, die die Pravention und Regression der Myokardfibrose zum Gegenstand haben — eine wichtige Determinante des pathologischen strukturellen Umbaus und der abnormen Myokardstarre.