Abstract 5363: Sustained Pharmacological βIIPKC Inhibition Is Cardioprotective In Late-stage Hypertrophy And End-stage Heart Failure In Two Rat Models
Previously, we found that βIIPKC levels increase during the transition from compensated hypertrophy to dysfunction in hearts from hypertensive Dahl salt-sensitive rats. We show here that a six-week treatment with βIIV5–3, a βIIPKC-specific inhibitor peptide that our lab has previously designed, prolongs survival in this model of hypertrophy and delays the transition from compensated hypertrophy to cardiac dysfunction in these hypertensive rats. We also show that a six-week treatment with βIIV5–3 in a post-myocardial infarction model also increased survival and improved fractional shortening from 14±2% in control-treated animals to 27±2%. Importantly, this chronic but mild inhibition of βII PKC using βIIV5–3 (60±8% inhibition of translocation and 62±9% inhibition of catalytic activity relative to control-treated animals) did not affect the activity of any other PKC isozymes, including αPKC and the closely related, βI PKC. We also found that in the post-myocardial infarction model, exercise tolerance was improved and cardiac hypertrophy was decreased in the βII V5–3-treated group vs. controls. Changes in the levels of the Ca2+-handling proteins, SERCA2 and the Na+/Ca2+ exchanger, seen in the control-treated heart failure rats were not observed in the βII PKC-treated rats, suggesting that βII PKC regulates calcium levels in the myocardium. In contrast, treatment with the selective inhibitor of βIPKC, an alternative splicing variant of βIIPKC, had no beneficial effects. Finally, we show that βIIV5–3 treatment improved calcium handling in isolated rat cardiomyocytes and enhanced contractility in isolated rat hearts. In conclusion, our data using two distinct in vivo models of heart failure (late-phase hypertrophy and end-stage ischemic heart disease) suggest that βIIPKC activation contributes to the pathology associated with heart failure and may be a potential therapeutic target for the treatment of this disease.
This research has received full or partial funding support from the American Heart Association, AHA Western States Affiliate (California, Nevada & Utah).