HIV transgene expression impairs K⁺ channel function in the pulmonary vasculature

Abstract

Human immunodeficiency virus (HIV) infection is an established risk factor for pulmonary arterial hypertension (PAH), however the pathogenesis of HIV-related PAH remains unclear. Since K+ channel dysfunction is a common marker in most forms of PAH, our aim was to analyse if the expression of HIV proteins is associated with impairment of K+ channel function in the pulmonary vascular bed. HIV transgenic mice (Tg26) expressing seven of the nine HIV viral proteins and wild type (Wt) mice were used. Hemodynamic assessment was performed by echocardiography and catheterization. Vascular reactivity was studied in endothelium-intact pulmonary arteries (PA). K+ currents were recorded in freshly isolated PA smooth muscle cells (PASMC) using the patch-clamp technique. Gene expression was assessed using RT-PCR. PASMC from Tg26 mice had reduced K+ currents and were more depolarized that those from Wt. While Kv1.5 currents were preserved, pH-sensitive non-inactivating background currents (IKN) were nearly abolished in PASMC from Tg26 mice. Tg26 mice had reduced lung expression of Kv7.1 and Kv7.4 channels and decreased responses to the Kv7.1 channel activator L634,373 assessed by vascular reactivity and patch-clamp experimental approaches. While we found pulmonary vascular remodelling and endothelial dysfunction in Tg26 mice, this was not accompanied by changes in hemodynamic parameters. In conclusion, the expression of HIV proteins in vivo impairs pH-sensitive IKN and Kv7 currents. This negative impact of HIV proteins in K+ channels, was not sufficient to induce PAH, at least in mice, but may play a permissive or accessory role in the pathophysiology of HIV-associated PAH.

Direct Effects of Cigarette Smoke in Pulmonary Arterial Cells alter Vascular Tone through Arterial Remodeling and Kv7.4 Channel Dysregulation

“…KCNQ (KCNQ1-5) genes encode a subfamily of voltage-gated K + channels, denoted Kv7.1-Kv7.5. These channels play a key role in the control of vascular tone in several blood vessels, including the pulmonary circulation [34,[71][72][73] In conclusion, our results prove that CSE has differential effects in pulmonary arteries compared to effects described in the airways. Furthermore, we corroborate the idea that CSE-induced vascular remodeling is not just a consequence of alveolar hypoxia and loss of capillary bed but can also be due to direct effects on the vascular bed.…”

“…In contrast, reduced K+ channel performance induces a more depolarized membrane potential in PASMCs, which leads to increased intracellular calcium, vasoconstriction, hypertrophy and proliferation [25][26][27][28][29]. Thus, impairment of K+ channels is considered a hallmark in the pulmonary vascular alterations associated with pulmonary hypertension and other respiratory conditions such as asthma and COPD [30][31][32][33][34][35]. However, the possible alteration of K+ channels by CSE in PASMC has been essentially unexplored.…”

Kv7 Channels in Lung Diseases

“…Linopirdine can also increase mesenteric vascular resistance and systemic arterial pressure (Mackie et al, 2008). Functional expression of Kv7 channels in the pulmonary circulation was later confirmed by others (Morecroft et al, 2009;Eid and Gurney, 2018;Mondejar-Parreño et al, 2018). As in the systemic circulation, KCNQ1 and especially KCNQ4 and KCNQ5 appear the most predominant KCNQ channels in the pulmonary circulation (Joshi et al, 2009;Morales-Cano et al, 2014;Sedivy et al, 2015;Mondejar-Parreño et al, 2018).…”

“…Functional expression of Kv7 channels in the pulmonary circulation was later confirmed by others (Morecroft et al, 2009;Eid and Gurney, 2018;Mondejar-Parreño et al, 2018). As in the systemic circulation, KCNQ1 and especially KCNQ4 and KCNQ5 appear the most predominant KCNQ channels in the pulmonary circulation (Joshi et al, 2009;Morales-Cano et al, 2014;Sedivy et al, 2015;Mondejar-Parreño et al, 2018). The lack of selective drugs for the different Kv7 subunits hinders identification of the functional impact of individual Kv7 members (Barrese et al, 2018).…”

“…The lack of selective drugs for the different Kv7 subunits hinders identification of the functional impact of individual Kv7 members (Barrese et al, 2018). Structurally related Kv7 enhancers such as retigabine and flupirtine (which activate all Kv7 isoforms except Kv7.1 channels) ( Barrese et al, 2018) and zinc pyrithione (which activate all Kv7 members but Kv7.3) have been shown to induce pulmonary vasodilation (Joshi et al, 2009;Morecroft et al, 2009;Sedivy et al, 2015;Eid and Gurney, 2018;Mondejar-Parreño et al, 2018). In addition, drugs that block all Kv7 channels (i.e., linopirdine and XE991) are able to contract PAs previously primed (Chadha et al, 2012;Sedivy et al, 2015) or not (Joshi et al, 2009), whereas selective Kv7.1 blockers HMR1556, L768, L673, and JNJ39490282 (Barrese et al, 2018) have no contractile effects in PAs (Chadha et al, 2012).…”