There is growing interest in the molecular cross-talk between the endocrine and cardiovascular systems, including the effects of hormones on cardiomyocte viability in models of ischemic and oxidative stress. However, current attention has focused on reproductive and metabolic hormones; the cardiac effects of calcium-regulating hormones (i.e., parathyroid hormone-related peptide (PTHrP)) have not been explored. To address this, we interrogated the effect of PTHrP on the viability of isolated adult mouse cardiomyocytes subjected to H
2
O
2
-induced oxidative stress. In
Aim 1
, myocytes from wild type (WT) C57 mice were incubated for 16 hrs with 100 nM PTHrP or vehicle and exposed to 100 μM H
2
O
2
for 15 min. Myocyte viability was significantly improved in PTHrP-treated cells
vs
vehicle control (70±12%
vs
20±15%; mean ± SD, p<0.01; Figure). Calcium sensing receptor and PTHrP signaling is purportedly associated with Mitogen-Activated Protein Kinases (MAPKs) and MAPK phosphatase-1 (MKP1). Accordingly, to achieve preliminary mechanistic insight into PTHrP-induced protection (
Aim 2
), we: (i) incubated WT cardiomyocytes with PTHrP (100 nM) and probed for expression of MKP1; and (ii) repeated the viability assay as described above using myocytes from adult MKP1 knockout (KO) mice. Incubation of WT myocytes with PTHrP evoked a 55% decrease in MKP1 expression. Moreover, myocytes from MKP1 KO mice were resistant to oxidative injury: viability was maintained at 78±12% in vehicle controls (mean ± SD, p<0.01
vs
the value of 20±15% in vehicle-treated WT cells), with no added benefit of PTHrP treatment (Figure). Finally (
Aim 3
), in both models (PTHrP treatment; MKP1 KO), the enhanced cell viability was accompanied by ~2-fold increases in Akt phosphorylation. These data provide novel evidence that: i) down-regulation of MKP1 affords profound protection against oxidative stress; and ii) PTHrP is cardioprotective, possibly via down-regulation of MKP1 and activation of Akt signaling.
Calcium-Sensing Receptor Endocytosis Links Extracellular Calcium Signaling to Parathyroid Hormone-Related Peptide Secretion via a Rab11a-Dependent and AMSH-Sensitive Mechanism
