Cyclic Adenosine Monophosphate in Acute Myocardial Infarction With Heart Failure

Abstract

C yclic adenosine monophosphate (cAMP) is a tightly regulated second messenger that is critically involved in many intracellular processes. In cardiomyocytes, the activation of a number of membrane receptors, notably ␤-receptors and muscarinic receptors, acts through stimulatory or inhibitory G-proteins (G␣s/G␣i) on adenylyl cyclase (AC), which synthesizes cAMP from ATP. cAMP is degraded by phosphodiesterases (PDE). Thereafter, cAMP activates protein kinase A (PKA), which, in turn, through phosphorylation of L-type calcium channels, ryanodine receptors, phospholamban, and troponin I, improves excitationcontraction coupling and increases heart rate, as well as contraction amplitude and relaxation. PKA also phosphorylates nuclear cAMP-response element binding proteins to activate transcription. 1 There are at least 9 isoforms of AC; the mammalian myocardium expresses mainly AC V and VI. AC V is the predominant isoform in adult cardiac tissue, whereas AC VI expression decreases with age. Both isoforms are phosphorylated by PKA and thereby inhibited, thus providing a feedback regulation and potential desensitization pathway. 2,3 Transgenic mice with cardiac-directed overexpression of AC VI have normal cAMP and cardiac function at rest but increased responses in both cAMP and function to ␤-adrenergic stimulation, 4 as confirmed in the present study by Takahasi et al. 5 Article p 388The prevailing notion is that increased myocardial cAMP in settings of acute myocardial ischemia is detrimental. In fact, ␤-adrenergic agonists that increase cAMP formation disrupt perfusion-contraction matching and promote infarction in controlled animal models of myocardial ischemia, both by increasing myocardial energetic requirements and by an unfavorable flow redistribution away from the ischemic subendocardium. 6 Apart from increasing infarct size, cAMP promotes ventricular tachyarrhythmias in ischemia/reperfusion. 7 Although increased cAMP acutely increases left ventricular function in heart failure, most trials with either ␤-adrenergic agonists or PDE inhibitors have revealed increased mortality, possibly secondary to tachyarrhythmias. 1 The present article by Takahashi et al 5 challenges the concept that cAMP in subacute myocardial infarction with heart failure is bad. They subjected transgenic mice with cardiac-directed overexpression of AC VI to permanent coronary ligation and found 17-fold-elevated AC protein content and 4.3-fold-increased cAMP formation, along with reduced mortality, over a 1-week observation period. The reduced mortality in the AC VI-overexpressing mice was associated with a nonsignificant increase in ventricular extrasystoles but reduced bradyarrhythmias. The better conduction properties in the AC VI-overexpressing mice were not mechanistically explained but are possibly related to connexin 43 expression, which is reduced in heart failure 8 and increased by catecholamines in a PKA-dependent manner. 9 Reduced mortality is a robust and undisputable end point in mice and humans, and in this respect, the present...

Targeted Inhibition of Cardiomyocyte Gi Signaling Enhances Susceptibility to Apoptotic Cell Death in Response to Ischemic Stress

“…16 The role of Gi signaling in the context of myocardial ischemia and the progression toward heart failure is not straightforward. 17,18 One salient characteristic of the failing heart is upregulation of G␣ i2 at the protein and transcript levels 19 ; to date, however, there has been controversy surrounding the beneficial or maladaptive nature of this upregulation. 16,20 To address Gi signaling in this regard, we have developed a Gi-selective inhibitory peptide to "functionally knock out" all GPCR-Gi-induced signals in the heart.…”

Designing Heart Performance by Gene Transfer

“…However, increased cAMP is associated with arrhythmias, which were not observed in the transgenic model. Thus the improved mortality observed in AC-VI transgenic mice may be due to 1) the close proximity of this isoform to the sarcolemma and 2) cAMP-dependent effects of AC-VI (324,479). It remains unclear whether gene delivery of AC-VI is capable of reversing LV morphological and functional remodeling, but this gene is garnering consideration for clinical heart failure therapy (324).…”

Myocardial protection in man—from research concept to clinical practice

“…Whether this would prevent against remodeling remains to be seen. Leineweber et al [188] point out that b-adrenergic agonist activation can be both detrimental and favorable in the setting of acute myocardial infarction. Actually the concept of ''yin and yang'' is operative in many aspects of cardioprotection in the context that an agent may be either beneficial or noxious according to the circumstances [189].…”