# Role of Non-visual Opsins in Light-dependent Apoptosis of Pulmonary Arterial Smooth Muscle Cells in Pulmonary Arterial Hypertension

> **NIH NIH F32** · JOHNS HOPKINS UNIVERSITY · 2020 · $61,265

## Abstract

PROJECT SUMMARY/ ABSTRACT:
Pulmonary arterial hypertension (PAH), a progressive and deadly condition characterized by pre-capillary
disease with vaso-occlusive lesions and severe elevations in pulmonary arterial pressure, is attributed to both
loss of vascular relaxation and severe vascular remodeling. Significant dysregulation of apoptosis, or
programmed cell death, in pulmonary arterial smooth muscle cells (PASMCs) prevents turnover of abnormal
PASMCs and contributes significantly to vascular remodeling. Currently approved treatments target
vasodilation and slow progression of PAH, but drugs targeting reversal of vascular remodeling, and particularly
cell death, that can serve as effective therapies to reverse disease have yet to be identified. We recently
discovered the presence photoreceptors, or opsins, in rodent systemic and pulmonary blood vessels and
elucidated the pathway by which they mediate vasorelaxation in response to blue light. In pulmonary arterial
smooth muscle cells (PASMCs), we recently found that blue light exposure also selectively induces cell death
in PASMCs from a model of PAH. In contrast, in normal PASMCs, apoptosis can be induced by blue light only
when G protein-coupled receptor kinase-2 (GRK2), a negative regulator of opsin activity, is inhibited. Thus, the
focus of my proposal is to explore this intriguing finding and elucidate the mechanism by which blue light
induces apoptosis. We will employ the Sugen-hypoxia rat model of severe PAH to isolate PASMCs used in in
vitro experiments. In Specific Aim 1, we will determine whether expression of opsin receptors is increased or
expression of GRK2 is decreased, in PAH PASMCs. In Specific Aim 2, we will measure intracellular K+ ([K+]i) to
determine if blue light exposure increases the susceptibility to apoptosis, in of PAH PASMC through efflux of
K+ via cyclic nucleotide-gated K+ channels, and in Specific Aim 3, we will measure cleaved (active) caspase-3
levels and activity to determine whether blue light exposure increases caspase-3 activity in PAH PASMCs.
With the completion of the research proposed in this application, we will characterize a completely novel,
wavelength-specific, light-activated molecular switch, which could be harnessed for treatment of PAH to
prevent and potentially reverse remodeling by selectively restoring apoptosis in abnormal PASMCs. The funds
from this award will not only allow for the training necessary for the applicant to realize this goal, but also
provide the opportunity to begin developing methods for in vivo application of the results.

## Key facts

- **NIH application ID:** 10025576
- **Project number:** 5F32HL149163-02
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Gautam Sikka
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $61,265
- **Award type:** 5
- **Project period:** 2019-09-13 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10025576

## Citation

> US National Institutes of Health, RePORTER application 10025576, Role of Non-visual Opsins in Light-dependent Apoptosis of Pulmonary Arterial Smooth Muscle Cells in Pulmonary Arterial Hypertension (5F32HL149163-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10025576. Licensed CC0.

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