The Riskier Lipid: What Is on the HORIZON for Lipoprotein (a) and Should There Be Lp(a) Screening for All?

PURPOSE OF REVIEW: Despite widespread targeting of cardiovascular risk factors, many patients continue to experience clinical events. This residual risk has stimulated efforts to develop novel therapeutic approaches to target additional factors underscoring cardiovascular disease. This review aimed to summarize existing evidence supporting targeting of Lp(a) as a novel cardioprotective strategy. RECENT FINDINGS: Increasing evidence has implicated lipoprotein (a) [Lp(a)] in the pathogenesis of both atherosclerotic and calcific aortic valve disease. Therapeutic advances have produced novel agents that selectively lower Lp(a) levels, which have now progressed to evaluate their impact on cardiovascular events in large clinical outcome trials. Evidence continues to accumulate suggesting that targeting Lp(a) may be effective in reducing cardiovascular risk. With advances in Lp(a) targeted therapeutics, clinical trials now have the opportunity to determine whether this strategy will be effective for high-risk patients.

Modified redox signaling in vasculature after chronic infusion of the insulin receptor antagonist, S961.

BACKGROUND: Type 2 diabetes and associated vascular complications cause substantial morbidity and mortality. It is important to investigate mechanisms and test therapies in relevant physiological models, yet few animal models adequately recapitulate all aspects of the human condition. OBJECTIVE: We sought to determine the potential of using an insulin receptor antagonist, S961, in mice for investigating vascular pathophysiology. METHODS: S961 was infused into mice for 4 weeks. Blood glucose was monitored, and insulin was measured at the end of the protocol. Blood pressure and pressor responses to vasodilators were measured in cannulated mice, and vascular reactive oxygen and nitrogen species were measured in isolated tissue. RESULTS: S961 infusion-induced hyperglycemia and hyperinsulinemia. There was evidence of increased vascular reactive oxygen and nitrogen species and modification of NO-mediated signaling. Pressor responses to a NO donor were attenuated, but responses to bradykinin were preserved. CONCLUSIONS: Infusion of S961, an insulin receptor antagonist, results in the production of a mouse model of type 2 diabetes that may be useful for investigating redox signaling in the vasculature of insulin-resistant mice over the short term. It is limited by both the transient nature of the hyperglycemia and incomplete functional analogy to the human condition.

Vasoactive actions of nitroxyl (HNO) are preserved in resistance arteries in diabetes.

Endothelial dysfunction is a major risk factor for the vascular complications of diabetes. Increased reactive oxygen species (ROS) generation, a hallmark of diabetes, reduces the bioavailability of endothelial vasodilators, including nitric oxide (NO·). The vascular endothelium also produces the one electron reduced and protonated form of NO·, nitroxyl (HNO). Unlike NO·, HNO is resistant to scavenging by superoxide anions (·O2─). The fate of HNO in resistance arteries in diabetes is unknown. We tested the hypothesis that the vasodilator actions of endogenous and exogenous HNO are preserved in resistance arteries in diabetes. We investigated the actions of HNO in small arteries from the mesenteric and femoral beds as they exhibit marked differences in endothelial vasodilator function following 8 weeks of streptozotocin (STZ)-induced diabetes mellitus. Vascular reactivity was assessed using wire myography and ·O2─ generation using lucigenin-enhanced chemiluminescence. The HNO donor, Angeli's salt, and the NO· donor, DEA/NO, evoked relaxations in both arteries of control rats, and these responses were unaffected by diabetes. Nox2 oxidase expression and ·O2─ generation were upregulated in mesenteric, but unchanged, in femoral arteries of diabetic rats. Acetylcholine-induced endothelium-dependent relaxation was impaired in mesenteric but not femoral arteries in diabetes. The HNO scavenger, L-cysteine, reduced this endothelium-dependent relaxation to a similar extent in femoral and mesenteric arteries from control and diabetic animals. In conclusion, HNO and NO· contribute to the NO synthase (NOS)-sensitive component of endothelium-dependent relaxation in mesenteric and femoral arteries. The role of HNO is sustained in diabetes, serving to maintain endothelium-dependent relaxation.

Inhibition of phosphodiesterase 2 augments cGMP and cAMP signaling to ameliorate pulmonary hypertension.

BACKGROUND: Pulmonary hypertension (PH) is a life-threatening disorder characterized by increased pulmonary artery pressure, remodeling of the pulmonary vasculature, and right ventricular failure. Loss of endothelium-derived nitric oxide (NO) and prostacyclin contributes to PH pathogenesis, and current therapies are targeted to restore these pathways. Phosphodiesterases (PDEs) are a family of enzymes that break down cGMP and cAMP, which underpin the bioactivity of NO and prostacyclin. PDE5 inhibitors (eg, sildenafil) are licensed for PH, but a role for PDE2 in lung physiology and disease has yet to be established. Herein, we investigated whether PDE2 inhibition modulates pulmonary cyclic nucleotide signaling and ameliorates experimental PH. METHODS AND RESULTS: The selective PDE2 inhibitor BAY 60-7550 augmented atrial natriuretic peptide- and treprostinil-evoked pulmonary vascular relaxation in isolated arteries from chronically hypoxic rats. BAY 60-7550 prevented the onset of both hypoxia- and bleomycin-induced PH and produced a significantly greater reduction in disease severity when given in combination with a neutral endopeptidase inhibitor (enhances endogenous natriuretic peptides), trepostinil, inorganic nitrate (NO donor), or a PDE5 inhibitor. Proliferation of pulmonary artery smooth muscle cells from patients with pulmonary arterial hypertension was reduced by BAY 60-7550, an effect further enhanced in the presence of atrial natriuretic peptide, NO, and treprostinil. CONCLUSIONS: PDE2 inhibition elicits pulmonary dilation, prevents pulmonary vascular remodeling, and reduces the right ventricular hypertrophy characteristic of PH. This favorable pharmacodynamic profile is dependent on natriuretic peptide bioactivity and is additive with prostacyclin analogues, PDE5 inhibitor, and NO. PDE2 inhibition represents a viable, orally active therapy for PH.

Activation of neuronal transient receptor potential vanilloid 1 channel underlies 20-hydroxyeicosatetraenoic acid-induced vasoactivity: role for protein kinase A.

A rise in intraluminal pressure triggers vasoconstriction in resistance arteries, which is associated with local generation of the vasoconstrictor 20-hydroxyeicosatetraenoic acid (20-HETE). Importantly, dysregulation of 20-HETE synthesis and activity has been implicated in several cardiovascular disease states, including ischemic disease, hypertension, and stroke; however, the exact molecular pathways involved in mediating 20-HETE bioactivity are uncertain. We investigated whether 20-HETE activates the transient receptor potential vanilloid 1 (TRPV1) and thereby regulates vascular function and blood pressure. We demonstrate that 20-HETE causes dose-dependent increases in blood pressure, coronary perfusion pressure (isolated Langendorff), and pressure-induced constriction of resistance arteries (perfusion myography) that is substantially attenuated in TRPV1 knockout mice and by treatment with the neurokinin 1 receptor antagonist RP67580. Furthermore, we show that both channel activation (via patch-clamping of dorsal root ganglion neurons) and vessel constriction are enhanced under inflammatory conditions, and our findings indicate a predominant role for protein kinase A-mediated sensitization of TRPV1 in these phenomena. Finally, we identify a prominence of these pathway in males compared with females, an effect we relate to reduced protein kinase A-induced phosphorylation of TRPV1. 20-HETE-induced activation of TRPV1, in part, mediates pressure-induced myogenic constriction and underlies 20-HETE-induced elevations in blood pressure and coronary resistance. Our findings identify a novel vasoconstrictor 20-HETE/TRPV1 pathway that may offer potential for therapeutic targeting in cardiovascular diseases associated with elevated 20-HETE implicated in dysregulated organ blood flow, such as stroke or hypertension.

Enhanced vasodilator activity of nitrite in hypertension: critical role for erythrocytic xanthine oxidoreductase and translational potential.

Elevation of circulating nitrite (NO2(-)) levels causes vasodilatation and lowers blood pressure in healthy volunteers. Whether these effects and the underpinning mechanisms persist in hypertension is unknown. Therefore, we investigated the consequences of systemic nitrite elevation in spontaneously hypertensive rats and conducted proof-of-principle studies in patients. Nitrite caused dose-dependent blood pressure-lowering that was profoundly enhanced in spontaneously hypertensive rats versus normotensive Wistar Kyoto controls. This effect was virtually abolished by the xanthine oxidoreductase (XOR) inhibitor, allopurinol, and associated with hypertension-specific XOR-dependent nitrite reductase activity localized to the erythrocyte but not the blood vessel wall. To determine whether these pathways translate to human hypertension, we investigated the effects of elevation of circulating nitrite levels in 15 drug naïve grade 1 hypertensives. To elevate nitrite, we used a dose of dietary nitrate (≈ 3.5 mmol) that elevated nitrite levels ≈ 1.5-fold (P<0.01); a rise shown previously to exert no significant blood pressure-lowering effects in normotensives. This dose caused substantial reductions in systolic (≈ 12 mm Hg) and diastolic blood pressures (P<0.001) and pulse wave velocity (P<0.05); effects associated with elevations in erythrocytic XOR expression and XOR-dependent nitrite reductase activity. Our observations demonstrate the improved efficacy of inorganic nitrate and nitrite in hypertension as a consequence of increased erythrocytic XOR nitrite reductase activity and support the concept of dietary nitrate supplementation as an effective, but simple and inexpensive, antihypertensive strategy.

Uteroplacental insufficiency and lactational environment separately influence arterial stiffness and vascular function in adult male rats.

Early life environmental influences can have lifelong consequences for health, including the risk of cardiovascular disease. Uteroplacental insufficiency causes fetal undernutrition and impairs fetal growth. Previously we have shown that uteroplacental insufficiency is associated with impaired maternal mammary development, compromising postnatal growth leading to hypertension in male rat offspring. In this study we investigated the roles of prenatal and postnatal nutritional environments on endothelial and smooth muscle reactivity and passive wall stiffness of resistance arteries of male rat offspring. Fetal growth restriction was induced by maternal bilateral uterine vessel ligation (restricted) on day 18 of pregnancy. Control offspring were from mothers that had sham surgery (control) and another group from mothers with their litter size reduced (reduced; litter size reduced to 5 at birth, equivalent to the restricted group). On postnatal day 1, offspring (control, restricted, and reduced) were cross-fostered onto control or restricted mothers. At 6 months, mesenteric and femoral arteries were studied using wire and pressure myography. In restricted-on-restricted rats, wall stiffness was increased, and sensitivity to phenylephrine and relaxation evoked by endothelium-derived hyperpolarizing factor and sodium nitroprusside were impaired in mesenteric arteries. In femoral arteries, relaxation to sodium nitroprusside was reduced, whereas wall stiffness was unaltered. Cross-fostering restricted offspring onto control mothers alleviated deficits in vascular stiffness and reactivity. Control or reduced offspring who suckled a restricted mother had marked vascular stiffening. In conclusion, prenatal and early postnatal environments separately influence vascular function and stiffness. Furthermore, the early postnatal lactational environment is a determinant of later cardiovascular function.