We previously showed that sodium tanshinone IIA sulfonate (STS) inhibited store-operated Ca²⁺ entry (SOCE) through store-operated Ca²⁺ channels (SOCC) via down regulating the expression of transient receptor potential canonical proteins (TRPC), which contribute to the formation of SOCC. The detailed molecular mechanisms by which STS inhibits SOCE and downregulates TRPC, however, remain largely unknown. We have previously shown that under hypoxic conditions, inhibition of protein kinase G (PKG) and peroxisome proliferator-activated receptor (PPAR) signaling axis results in the up-regulation of TRPC. This suggests that strategies targeting the restoration of this signaling pathway may be an effective treatment strategy for pulmonary hypertension. In this study, our results demonstrated that STS treatment can effectively prevent the hypoxia mediated inhibition of the PKG-PPAR signaling axis in rat distal pulmonary artery smooth muscle cells (PASMCs) and distal pulmonary arteries (PA). These effects of STS treatment were blocked by pharmacological inhibition or specific small interfering RNA knockdown of either PKG or PPAR. Moreover, targeted PPAR agonist markedly enhanced the beneficial effects of STS. These results comprehensively suggest that STS treatment can prevent hypoxia mediated increases in intracellular calcium homeostasis and cell proliferation, by targeting and restoring the hypoxia-inhibited PKG-PPAR signaling pathway in PASMCs.