Increase in G _iα Protein Accompanies Progression of Post-Infarction Remodeling in Hypertensive Cardiomyopathy

Abstract

Abstract-Hypertensive cardiac hypertrophy and myocardial infarction (MI) are clinically relevant risk factors for heart failure. There is no specific information addressing signaling alterations in the sequence of hypertrophy and post-MI remodeling. To investigate alterations in ␤-adrenergic receptor G-protein signaling in ventricular remodeling with pre-existing hypertrophy, MI was induced by coronary artery ligation in Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). Ten weeks after the induction of MI, the progression of left ventricular dysfunction and increases in plasma atrial natriuretic peptide (ANP) and cardiac ANP mRNA were more pronounced in SHR than WKY. In addition, the impaired contractile response to ␤-adrenergic stimulation was observed in the noninfarcted papillary muscle isolated from SHR. Immunochemical G s␣ protein and ␤-adrenoceptor density were not significantly altered by MI in both strains. However, immunochemical G i␣ was increased (1.5-fold) in the noninfarcted left ventricle of the SHR in which infarction had been induced when compared with that in SHR that underwent sham operation. This increase was observed especially in rats with a high plasma ANP level. Furthermore, there was a positive correlation between G i␣ and the extent of post-MI remodeling in WKY. A similar correlation between G i␣ and the extent of hypertensive hypertrophy was observed in SHR. In conclusion, the vulnerability of hypertrophied hearts to ischemic damage is greater than that of normotensive hearts. An increase in G i␣ could be one mechanism involved in the transition from cardiac hypertrophy to cardiac failure when chronic pressure overload and loss of contractile mass from ischemic heart disease coexist. Key Words: myocardial infarction Ⅲ cardiomegaly Ⅲ ventricular remodeling Ⅲ G proteins Ⅲ atrial natriuretic factor V entricular remodeling after myocardial infarction (MI) is increasingly recognized as being one of the most important causes of chronic heart failure. 1 To define the pathophysiological mechanisms underlying that process, coronary artery ligation in the rat model has been well studied. 2,3 This classic model is attractive because the structural and functional alterations that occur during post-MI remodeling (eg, hypertrophy of noninfarcted myocardium, an increase in collagen content, and progressive contractile dysfunction) are similar to those alterations observed in humans. 3 However, in addition to ischemic damage, chronic stress that is due to residual coronary stenosis and, in particular, systemic hypertension, is often involved in the progression of human ischemic cardiomyopathy. The coronary artery ligation model in which there are no additional pathologic factors such as those cited may not be applicable to clinical settings.Hypertensive cardiac hypertrophy is another major cause of heart failure. 4 Although hypertrophy is thought of initially as being a compensatory mechanism, chronic pressure overload results in the decompensation of the hypertrophied heart. 5 In addi...

Susceptibility to systolic dysfunction in the myocardium from chronically infarcted spontaneously hypertensive rats

“…This is consistent with the finding in the present study of a reduced LV systolic chamber function noted after a MI in SHR compared with WKY rats only in the presence of an adrenergic stimulus. Importantly, in contrast to a previous study where it was unclear whether similar changes occurred in WKY rats (14), the present study suggests that systolic function in the presence of an adrenergic stimulus is reduced in SHR compared with WKY rats post-MI. Moreover, in a previous study showing a reduction in systolic function in the presence of an adrenergic Fig.…”

“…Viable myocardium from SHR, but not WKY rats, with a MI has been previously reported to develop upregulated G i proteins, a change that may translate into a reduced contractile response to an adrenergic stimulus (14). This is consistent with the finding in the present study of a reduced LV systolic chamber function noted after a MI in SHR compared with WKY rats only in the presence of an adrenergic stimulus.…”

“…Irrespective of discrepancies in normotensive hearts, the present study provides clear evidence that the hypertensive heart is susceptible to decreases in regional myocardial systolic function in tissue remote from an infarct post-MI when studied 6 to 7 mo after a MI. These data are in keeping with a reduced adrenergic inotropic response of the papillary muscle in SHR after a MI (14).…”

“…In this regard, in normotensive animals, some studies have demonstrated the importance of a decrease in regional systolic dysfunction measured in noninfarcted and remodeled myocardial tissue remote from a MI (4, 6, 17-19, 21, 35, 40), changes that may be related to a number of mechanisms (9,35). Because hypertensive hearts compared with normotensive hearts are more susceptible to alterations in viable-tissue adrenergic-signaling post-MI (14) and to apoptosis in general (36), this may increase the chances of myocardial systolic dysfunction occurring in remote cardiac tissue. The aim of the present study was, therefore, to assess whether the hypertensive heart compared with the normotensive heart is more susceptible to the development of myocardial dysfunction in viable cardiac tissue post-MI and the potential mechanisms thereof and whether this effect contributes toward global pump dysfunction.…”

Gene expression of adrenomedullin in failing myocardium: comparison to atrial natriuretic peptide

“…All experiments were performed in accordance with the German animal protection law. Male SHR (age ϭ 16 wk; Haarlan Winkelman) were anesthesized, and a thoracotomy was performed as described (17). The left coronary artery was ligated 2 mm beneath its origin.…”