Pharmacological options to protect the aged heart from ischemia and reperfusion injury by targeting the PKA-BKCa signaling pathway

作者：Heinen Andre^*; Stroethoff Martin; Schmidt Anika; Stracke Nadine; Behmenburg Friederike; Bauer Inge; Hollmann Markus W; Huhn Ragnar

来源：Experimental Gerontology, 2014, 56: 99-105.

DOI：10.1016/j.exger.2014.03.029

• Myocardial infarction
• Cardioprotection
• Aging
• Protein kinase A
• Large-conductance Ca2+ sensitive K+ channel

The beneficial effects of many cardioprotective strategies including ischemic or pharmacological conditioning are reduced in the aged heart. The underlying reason(s) for the age-dependent loss of cardioprotection is unclear. Recently, we demonstrated that protein kinase A (PKA) dependent cardioprotection is lost in the aged heart. However, activation of large-conductance Ca2+-sensitive K+ (BKCa) channels, a putative PICA downstream target, initiated cardioprotection also in the aged heart. Therefore, we aimed to investigate whether 1) BKCa channels are critically involved in PICA activation induced cardioprotection and 2) the age-dependent loss of cardioprotection is caused by differences in PICA regulation. %26lt;br%26gt;Using an in vivo rat model with regional myocardial ischemia, we treated young (2-4 months) and aged (22-24 months) Wistar rats with PICA activator forskolin, BKCa channel activator NS1619 and/or BKCa channel blocker iberiotoxin. %26lt;br%26gt;Forskolin induced infarct size reduction was 1) age-dependent and 2) prevented by iberiotoxin. The effect of forskolin on myocardial PICA activity was comparable in young and aged animals. In addition, NS1619 initiated cardioprotection also in the aged heart both when administered before ischemia and during early reperfusion phase. %26lt;br%26gt;Activation of BKCa channels is critically involved in forskolin induced cardioprotection. The age-dependency of forskolin induced cardioprotection is not caused by age-dependent differences in PICA activation. Pharmacological targeting of BKCa channels before or after myocardial ischemia is a promising therapeutic strategy to protect the aged heart from ischemia and reperfusion injury.

• 出版日期2014-8