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Page 10 of 22 Strassheim et al. Vessel Plus 2018;2:29 I http://dx.doi.org/10.20517/2574-1209.2018.44

tirely due to increased CM cell size, rather than proliferation. The adult heart is 56% CM, 27% fibroblasts,
[187]
10% VSMC, and 7% ECs, and these ratios change little between the four chambers . During PH, the ra-
[188]
tios of fibroblasts increases, and the ratio of ECs/CMs decreases . The transition to heart failure has been
linked to endothelial dysfunction due to insufficient reparative angiogenesis - a loss of capillaries supplying
cardiac myocytes with O , leading to capillary pruning, inflammation, and ROS production [147-149,188-193] .
2
Pathological role of GPCRs in cardiac myocyte with respect to RV failure
2+
The hypertrophy response is engaged when increased Ca - and cAMP-dependent contractile signals
lead to activation of NFAT, MEF2, and GATA . These signals are driven by GPCR agonists, such as Ang
4
II, thrombin, ET1, PGF2a, b-AR [194-197] . Typical gene expression changes include decreased expression of
2+
sarcoplasmic reticulum Ca re-uptake channel (SERCA2), increased expression of slow twitch contrac-
tile protein myosin heavy chain b9 (b-MHC, a.k.a. MyH7), and decreased expression of the fast twitch
a-MHC/MyH6, amongst others [198,199] . The transcription factor, Egr-1 has been linked to the down regula-
tion of cardiac SERCA2 in hypertrophy and was found to be overexpressed in PAs of PH patients [200-202] .
2+
GPCR-induced increase in intracellular Ca stimulates PKD activity, promoting nuclear export of histone
deacetylase 5 (HDAC5), thereby activating MEF2 to initiate hypertrophic gene program [203,204] . GPR91, a
receptor for succinate expressed in CMs, promotes cardiac hypertrophy by coupling to G/G -PI3K-Akt sig-
q
i
naling [205,206] . Succinate may be accumulated during cardiac remodeling due to changes in metabolism, and
when released from the cells, promotes positive feedback loop by activating GPR91 leading to hypertrophy,
[188]
or as also reported, to CM apoptosis via caspase3 .

Protective role of GPCRs in cardiac myocyte with respect to RV failure
The estrogen-activated GPER, found in CM, has been considered cardio-protective in a PI3K-Akt-depen-
dent mechanism [207,208] . RGS proteins 2, 4, 10, 14 modulate cardiac hypertrophy by inhibiting the G /G -
i
q
PLCb-Ca signaling axis. PKG activates RGS2 by phosphorylation, inhibiting G , G , and G signaling,
2+
s
q
i
which in turn, attenuates b-AR-induced hypertrophy and that of other GPCRs [209-212] . Atrial natriuretic
peptide (ANP) and brain natriuretic peptide (BNP) exert CV protective actions by the activation of cGMP-
2+
dependent PKG, which phosphorylates and activates RGS4, aiding its inhibition of GPCR-G -PLCb-Ca
q
[213]
axis . RGS6 promotes cardiac myocyte apoptosis associated with decompensation due to its capacity to
[214]
[215]
increase ROS . RGS10 inhibits the cardiac hypertrophy induced by Ang II . RGS14 protects against
[216]
aortic banding-induced cardiac hypertrophy and fibrosis, decreasing ERK1/2 hypertrophy signals .
ACTION OF GPCRS ON ENDOTHELIAL CELLS WITH RESPECT TO RV FAILURE
ED, occurring in failing RV, interconnects with fibrosis, as this appears to be a factor in the decreased
capillary density-ED observed in hypertrophy and with the altered metabolism of CM, critical towards
HF [217,218] . ED can result in potentially uncontrolled inflammation of local RV tissue and in turn can lead
to EC apoptosis, down regulation of eNOS and PGIS. TGF-b, which is pathologic in PH, is induced by
inflammation, promotes lung and heart fibrosis, but also promotes ED by inhibiting differentiation of en-
dothelial progenitor cells (EPCs) into ECs to repopulate damaged endothelium, counteracting the effects of
endothelium protective GPCR ligand, apelin [219,220] . Cardiovascular protective GPER is found in ECs, pro-
motes angiogenesis, and could be significant in defending against endothelial dysfunction [207,221,222] .

VASCULAR FIBROBLASTS AND CARDIAC FIBROSIS
Cardiac fibrosis, seen in animal models of PH, involves expansion of fibroblast populations, their dif-
[198]
ferentiation to myofibroblast, and the stiffening of the extracellular matrix by synthesis of collagens .
[175]
Fibroblasts also can derive from EMT via conversion of EC to fibroblasts . GPCRs promoting cardiac
2+
fibrosis include G -PLC-Ca - coupled 5-HT , Ang II, and endothelin CPCRs. The thrombin receptor,
2B
q
PAR1 is the most highly expressed GPCR in cardiac fibroblasts, therefore is a potentially important pro-
fibrotic GPCR [223-225] . P Y -purinergic receptors are reported to enhance pressure overload-induced fibrosis
2 6