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Increase in G(i alpha) protein accompanies progression of post-infarction remodeling in hypertensive cardiomyopathy
I Kouchi1, O Zolk, F Jockenhövel
1Klinik III für Innere Medizin, Universität zu Köln, Germany.
Insights
Spontaneously hypertensive rats with pre-existing cardiac hypertrophy show greater vulnerability to myocardial infarction (MI). Increased inhibitory G-protein alpha (G(i alpha)) signaling may contribute to heart failure progression after MI in these hearts.
Area of Science:
- Cardiovascular Physiology
- Molecular Cardiology
- G-Protein Signaling
Background:
- Hypertensive cardiac hypertrophy and myocardial infarction (MI) are significant risk factors for heart failure.
- Limited understanding exists regarding signaling pathway alterations during the progression from hypertrophy to post-MI remodeling.
Purpose of the Study:
- To investigate changes in beta-adrenergic receptor G-protein signaling in ventricular remodeling in the context of pre-existing cardiac hypertrophy.
- To compare the effects of MI on cardiac function and signaling in normotensive and spontaneously hypertensive rat models.
Main Methods:
- Myocardial infarction (MI) was induced via coronary artery ligation in Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR).
- Cardiac function, plasma and cardiac atrial natriuretic peptide (ANP) levels, and G-protein signaling components (G(s alpha), G(i alpha), beta-adrenoceptor) were assessed 10 weeks post-MI.
Main Results:
- SHR exhibited more pronounced left ventricular dysfunction and elevated ANP levels post-MI compared to WKY.
- Impaired beta-adrenergic contractile response was noted in SHR non-infarcted papillary muscles.
- A significant 1.5-fold increase in G(i alpha) was observed in the non-infarcted ventricle of MI-induced SHR, particularly in those with high ANP levels.
- G(i alpha) levels correlated positively with the extent of post-MI remodeling in WKY and hypertensive hypertrophy in SHR.
Conclusions:
- Hypertrophied hearts are more susceptible to ischemic damage than normotensive hearts.
- Increased G(i alpha) signaling may represent a key mechanism in the transition from cardiac hypertrophy to heart failure when combined with chronic pressure overload and ischemic injury.
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 beta-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 beta-adrenergic stimulation was observed in the noninfarcted papillary muscle isolated from SHR. Immunochemical G(s alpha) protein and beta-adrenoceptor density were not significantly altered by MI in both strains. However, immunochemical G(i alpha) 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 alpha) and the extent of post-MI remodeling in WKY. A similar correlation between G(i alpha) 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 alpha) 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.