CaSR in pulmonary hypertension Flashcards
What is pulmonary hypertension
It is MAP above 25 mmHg at rest
What is PH prevalence
It occurs in about 6-26 cases per million, making it a ‘rare’ condition, however, the incidence and prevalence may be underestimated due to incorrect diagnosis or undiagnosed patients (NHS England 2017)
What are the main features
There are about 5 sub-categories of PAH however, all forms are characterised by increased vascular remodelling, arterial wall stiffening and sustained vasoconstriction. These changes lead to proliferation os smooth muscle cells, and if untreated, patients survive only about 2.8 years from diagnosis
What is the CaSR
It is a GPCR with a venus flytrap extracellular binding domain, which upon activation causes conformational changes to allow activation or inhibition of various molecular pathways. It is a low affinity receptor, with high cooperation, and responds to minimal changes in blood calcium levels. It was thought to be only a PTH regulator until 1997, and now its role as a blood calcium sensor and regulator is well established
Yamamura et al 2012
Based on evidence from Zhang et al 2007 that resting calcium is increased in patients with IPAH, compared to normal healthy controls, to determine whether this rise in calcium was CaSR dependent, they isolated human PASM from patients with IPAH. They then compared them with PASM from controls and their findings showed that the expression of CaSR was increased. When spermine was added to the cells, there was a further rise in cytosolic calcium in the IPAH cells only and not the controls. Using siRNA to reduce the expression of CaSR, there was a reduction in the cytosolic calcium as well as a reduction in the cell proliferation.
Interestingly, when the CaSR was over expressed in the control PASM, there was a modelling of this to the IPAH, and the cytosolic calcium and proliferation increased
Yamamura et al 2012
They then performed in vitro studies in animal models of PH using rat models of MCT PH and Hypoxia induced PH to test the effect of calcylitics inserted intraperitoneally on the progression of PH. Their study showed that compared to vehicle controls, the addition of the calcilytic NP 2134 caused a reduction in the development of RVH and PAH.
These findings suggest a potential role for use of calcylytics to prevent PAH
Why are in vitro studies in animal models of PH using rat models of MCT PH and Hypoxia induced PH to test the effect of calcylitics by Yamamura et al 2012 good
Because a subset of patients with PH who do not respond to a vasodilatory challenge are not able to be treated with CCBs thus there is no current therapeutic for them
Yamamura et al 2015
Based on this rationale, the same group in 2015 developed a calcyltic CALHEX and NPS2134. By the use of these drugs on IPAH cells, there was a reduction in the amount of proliferation, and an attenuation of the increased cytosolic calcium leak.
Greenberg et al 2016
This would have been a potential target however, Greenberg et al demonstrated that in freshly isolated single rabbit mesenteric artery smooth muscle cells, Calhex-231 and NPS 2143 inhibited whole-cell VGCC currents. Their data suggests that these observations might result from inhibition of VGCCs by calcilytics rather than through CaSR inhibition. In agreement, several VGCC antagonists have been shown to inhibit proliferation of VSMCs in IPAH e.g. Sitbon et al 2005 and this is why they are used for current treatment
It is likely that molecular similarities account for this, as NPS 2143, Calhex-231, and Calindol are structurally-related to the non-dihydropyridine CCB like verapamil sharing a positively charged amino group
Tang et al 2016
They suggest that CaSR functionally couples with TRPV6 in PASM from IPAH patients and animals with experimental PAH. Blocking TRPV6 with siRNA, there was an inhibition in the calcium rise in cytosolic calcium, and the overexpression of both TRPV6 and CaSR in normal cells lead to s dramatic increase in intracytosolic calcium compared to either alone.
Yamamura et al 2016
Sildenafil + TRPV6
