Exploring Endothelial KCa Channel Activation as a Novel Strategy to Restore Cardiac Function Following Acute Myocardial Infarction in Mice

Endothelial dysfunction (ED) is a common underlying feature of several premorbid conditions (e.g. obesity, Type 2 Diabetes (T2D), atherosclerosis, hypertension) associated with the development of myocardial infarction (MI). The ability of an artery to dilate properly and oppose plaque formation within the vascular wall is compromised by ED, which ultimately leads to reduced blood flow. In the coronary circulation, ED can decrease blood supply to the working myocardium and the resulting prolonged ischemia can promote MI. Recent studies from our group have demonstrated that a small molecule activator of endothelial KCa2.3 and KCa3.1 channel activity (i.e. SKA‐31) improves agonist‐evoked vasodilation in resistance arteries from multiple vascular beds and species, and this effect remains robust in arteries from T2D tissues. We have further observed that prolonged administration of SKA‐31 to aged rats improves both their cardiac and vascular functions. Thus, the goal of this project is to investigate the potential cardio‐protective effects of SKA‐31 in male mice (12‐15 weeks of age, C57B1/6 strain) following an acute MI induced by permanent surgical ligation of the left‐anterior descending coronary artery. Within 48 h post‐surgery, MI and sham surgery mice were treated orally with either vehicle or 10 mg/kg of SKA‐31 daily for 6 weeks. Myocardial damage in MI mice was confirmed by histological staining. Echocardiographic assessment of cardiac function 4 weeks post‐surgery revealed that Ejection Fraction (EF) and Fractional Shortening (FS) were similar in sham animals treated with either vehicle or SKA‐31 (Table 1). Similar results were observed for measurements of end systolic volume (ESV) and end diastolic volume (EDV). In contrast, the MI animals treated with vehicle displayed ~50% decreases in EF and FS, and significantly larger values for ESV and EDV. These functional and structural parameters thus confirm the presence of sustained cardiac dysfunction in the MI mice. Treatment of MI mice with SKA‐31 did not lead to improvements in EF, FS, ESV or EDV compared with vehicle treated animals. Our preliminary findings indicate that SKA‐31 treatment did not affect the healthy cohort, but also did not improve gross cardiac function in the MI group. Recent data indicate that an acute MI is typically followed by a robust inflammatory response within the injured myocardium that peaks 3 days post‐MI and declines to baseline by 7‐9 days. We speculate that this local immune response is exacerbated by SKA‐31 administration within 48 h post‐injury, thereby negating any potential benefit of SKA‐31 at the level of the vasculature. Delaying SKA‐31 administration to coincide with the full decline of the local immune response may prove more effective in restoring cardiac function.

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