Metabolic actions of angiotensin II and insulin: a microvascular endothelial balancing act

Abstract

Metabolic actions of insulin to promote glucose disposal are augmented by nitric oxide (NO)-dependent increases in microvascular blood flow to skeletal muscle. The balance between NO-dependent vasodilator actions and endothelin-1-dependent vasoconstrictor actions of insulin is regulated by phosphatidylinositol 3-kinase-dependent (PI3K)--and mitogen-activated protein kinase (MAPK)-dependent signaling in vascular endothelium, respectively. Angiotensin II acting on AT₂ receptor increases capillary blood flow to increase insulin-mediated glucose disposal. In contrast, AT₁ receptor activation leads to reduced NO bioavailability, impaired insulin signaling, vasoconstriction, and insulin resistance. Insulin-resistant states are characterized by dysregulated local renin-angiotensin-aldosterone system (RAAS). Under insulin-resistant conditions, pathway-specific impairment in PI3K-dependent signaling may cause imbalance between production of NO and secretion of endothelin-1, leading to decreased blood flow, which worsens insulin resistance. Similarly, excess AT₁ receptor activity in the microvasculature may selectively impair vasodilation while simultaneously potentiating the vasoconstrictor actions of insulin. Therapeutic interventions that target pathway-selective impairment in insulin signaling and the imbalance in AT₁ and AT₂ receptor signaling in microvascular endothelium may simultaneously ameliorate endothelial dysfunction and insulin resistance. In the present review, we discuss molecular mechanisms in the endothelium underlying microvascular and metabolic actions of insulin and Angiotensin II, the mechanistic basis for microvascular endothelial dysfunction and insulin resistance in RAAS dysregulated clinical states, and the rationale for therapeutic strategies that restore the balance in vasodilator and constrictor actions of insulin and Angiotensin II in the microvasculature.

Keywords: Angiotensin II; Endothelial dysfunction; Insulin resistance; Nitric oxide.

Figure 1. Insulin signal transduction pathways regulating nitric oxide and endothelin-1 production in endothelium

PI 3-kinase branch of insulin signaling regulates NO production and vasodilation in vascular endothelium. MAP-kinase branch of insulin signaling controls secretion of endothelin-1 (ET-1) in vascular endothelium. eNOS, endothelial nitric oxide synthase; IRS, insulin receptor substrate; MEK, MAPK kinase; PDK, phosphoinositide-dependent protein kinase.

Figure 2. Summary of endothelial signaling pathways involved in Angiotensin II modulation of vascular tone

Angiotensin II activates AT₁R and AT₂R in the endothelium. Activation of the AT₂R increases intracellular acidosis and plasma kallikrein levels which induces the release of bradykinin and binding to the bradykinin receptor (B₂R). Bradykinin activates endothelial nitric oxide synthase (eNOS) to produce NO. AT₁R activates NADPH oxidase, a major source for ROS production. ROS in small amounts activates cSrc that subsequently activates eNOS. Chronic AT₁R activation leads to excessive ROS production that activates PYK2 to inactivate eNOS, reduces BH₄ and L-arginine levels, increases cellular ADMA concentrations, and causes eNOS “uncoupling”. AT₁R stimulates PKC and Ras/Raf/ERK pathway to increase ET-1 expression. Ang II-induced activation of PLA₂ increases synthesis of vasodilator and vasoconstrictor prostanoids. AT₁R, angiotensin II type receptor type 1; AT₂R, angiotensin II type receptor type 2; EET, epoxyeicosatrienoic acid; AA, arachidonic acid; PLA₂, phosholipase A₂; PKC, protein kinase C; ROCK, RhoA kinase; ERK, extracellular signal-regulated kinase; PYK2; proline-rich tyrosine kinase 2; p38, p38 mitogen activated protein kinase; COX, cyclooxygenase; AP-1, activator protein-1; TxA₂, thromboxane A₂; NO, nitric oxide; ET-1, endothelin-1; BH4, tetrahydrobiopterin; BH2, dihydrobiopterin; ADMA, asymmetric dimethylarginine; DDAH, dimethylarginine dimethylaminohydrolase; DHFR, dihydrofolate reductase; and CYPE, cytochrome P450 epoxygenase.

Figure 3. Signaling pathways mediating angiotensin II-induced pathway selective insulin resistance in PI3K signaling

Stimulation of AT₁R activates PKC, ERK, JNK, and p70S6K to inhibit IRS/PI3K/Akt/eNOS pathway. Increased oxidative stress “uncouples” eNOS and reduces NO bioavailability. Chronic activation of AT₁R decreases NO production, increases endothelial ET-1 expression, and creates an imbalance between vasodilator and vasoconstrictor actions of insulin. AT₁R, angiotensin II type receptor type 1; PKC, protein kinase C; IRS, insulin receptor substrate; ERK, extracellular signal-regulated kinase; JNK, C-Jun N-terminal kinase; p70S6K, p70 ribosomal S6 kinase; AP-1, activator protein-1; NO, nitric oxide; and ET-1, endothelin-1.