Insulin-initiated PI3K–Akt–eNOS–NO survival signalling and cardiovascular protection. Insulin binds to cell membrane insulin receptor, leading to the activation of mainly two signalling pathways: Ras–MAPK, which results in cell proliferation; and PI3K–Akt–eNOS, which results in metabolic modulation and cardiovascular protection. Among the insulin-activated signalling cascades, PI3K–Akt–eNOS–NO represents a special link between insulin and the cardiovascular system with regard to health and pathology. Activation of this signalling cascade, together with other Akt-activated molecules (such as GSK-3β, mTOR and p70S6 kinase), elicits pro-survival and cardiovascular protective effects, including vasodilatation, anti-apoptosis, anti-inflammation, and anti-oxidative/nitrative stress.
Abbreviations: Akt, protein kinase B; eNOS, endothelial nitric oxide synthase; ET-1, endothelin-1; GLUT4, glucose transporter 4; GSK, glycogen synthase kinase; IRS, insulin receptor substrate; MAPK, mitogen-activated protein kinase; mTOR, the mammalian target of rapamycin; PI3K, phosphatidylinositol 3′-kinase; PMN, polymorphonuclear neutrophil; and ROS, reactive oxygen species.
Fatty acid-induced mitochondrial uncoupling and impaired cardiac efficiency in the Type 2 diabetic heart
In Type 2 diabetes, cardiac mitochondrial dysfunction likely contributes to the development of contractile dysfunction. Myocardial mitochondrial energetics is compromised via a number of potential mechanisms, including oxidative damage, impairment in mitochondrial calcium handling, potentially maladaptive mitochondrial proliferation, and remodelling and post-translational modification of the mitochondrial proteome. A consistent observation in Type 2 diabetic hearts is decreased cardiac efficiency, which results from derangements in cardiac energy substrate metabolism and subsequent impairment in mitochondrial energetics. Increased delivery of serum fatty acids to the heart may result in increased cardiac fatty acid uptake and mitochondrial oxidation. The increase in reducing equivalent delivery to the electron transport chain (ETC) acting in concert with impaired ETC function leads to increased mitochondrial ROS production, which activates UCPs and ANT to increase proton leak into the mitochondrial matrix. Increased proton conductance via UCP and ANT will partially bypass the F0F1-ATPase.
Thus, coupling of ATP synthesis to oxygen consumption will be decreased, i.e. mitochondrial uncoupling will be increased. Mitochondrial uncoupling might further increase fatty acid oxidation. Moreover, mitochondrial uncoupling increases mitochondrial oxygen consumption. Since the increase in oxygen consumption represents uncoupled respirations, ATP synthesis would not increase proportionately. Thus, cardiac efficiency (CE), defined as cardiac work per unit of oxygen consumption, will be reduced, leading to a subsequent cardiac energy deficit that may ultimately contribute to contractile dysfunction.
Abbreviations: FAO, fatty acid oxidation; GO, glucose oxidation; ROS, reactive oxygen species; UCP, uncoupling protein; ANT, adenine nucleotide translocator.
High glucose, NO, and adenosine: a vicious circle in chronic hyperglycaemia.
HUVEC isolated from gestational diabetic pregnancies show a reduced adenosine transport activity via hENT1. This effect of gestational diabetes leads to extracellular accumulation and a higher bioavailability of this nucleoside to activate the A2a adenosine receptor subtype. The intracellular signalling cascade triggered by A2a purinoreceptor activation by adenosine results in an increased l-arginine transport activity via hCATs and increased NO synthesis by eNOS. The intracellular second messengers involved in the effect of adenosine include activation of protein kinase C (PKC) and 42/44 kDa mitogen-activated protein kinases (P42/44mapk), which then activate (+) l-arginine transport. The up-regulation in the endothelial l-arginine/NO pathway by adenosine is associated with an increase in NO. NO activates hCHOP and C/EBPα transcription factor complex formation, which migrates to the nucleus of the endothelial cells and binds, as a complex, to a consensus sequence located on the promoter region of the SLC29A1 gene (for hENT1).
This phenomenon results in reduced transcriptional activity of the SLC29A1 promoter, leading to reduced levels of the hENT1 mRNA and protein. As a consequence, a decreased hENT1 transport-like activity could result in reducing the removal of the endogenous nucleoside adenosine from the extracellular medium in HUVEC. The reduced adenosine transport via hENT1 detected in HUVEC from gestational diabetes could also result from the inhibition (−) by PKC or P42/44mapk. Notably, hyperglycaemia (glucose) may be proposed as a regulator of the illustrated vicious circle since it might increase (+) both eNOS and NO levels. hCHOP, a key transcriptional regulator of the SLC29A1 gene, has been demonstrated to be increased (+) by high glucose and diabetes.
Cardiomyocyte substrates utilization. (A) Healthy cardiomyocyte. Cardiomyocyte mainly uses FAs that enter into the cell and are converted in the mitochondria through the carnitine palmitoyltransferase type 1 and type 2 (CPT-1 and CPT-2), and the carnitine acylcarnitine translocase (CT) before being used by β-oxidation (β-Ox) to produce FADH2, H22, reduced form of flavine adenine dinucleotide; NADH, reduced form of nicotinamide adenine dinucleotide.
Disruption of fuel servicing in the myocardium: from ‘eutaxy and efficiency’ to ‘ataxy and inefficiency’
Deletion of PGC-1β leads to disruption of mitohormesis and arrhythmias in cardiomyocytes.
A tentative scheme is shown that depicts how PPAR-γ or PGC-1s stimulation and suppression modulate electrical activity in cardiomyocytes. For biological activity, PPAR-γ needs coactivation by PGC-1α/β. These coactivators are inducible and play a vital role in cellular ATP production and mitochondrial function.
Exogenous stress stimulates the expression of chemokines and adhesion molecules in the heart. These molecules promote atrial fibrosis on the one hand, and macrophage recruitment and inflammation on the other, which result in heart failure and arrhythmias substrate formation.
The suppression or deletion of PGC-1β seems to result in variable electrical instabilities and arrhythmias, especially during adrenergic stress. An imbalance of mitochondrial ATP production is noted as well, which is arrhythmogenic by itself. The stimulation of PPARγ; blocks stress-induced expression of chemokines and adhesion molecules. The recruitment of macrophages from storage sites such as splenic red pulp (red bar) is also suppressed, resulting in an improvement of atrial fibrosis and mitochondrial function. Details of signaling cascades mediated by the PPARγ-PGC-1 axis that leads to electrical instability are waiting to be elucidated.