Grant: Operating Grant

Conditions such as hypertension or heart attack increase the risk of heart failure. An intermediate step between these conditions and heart failure is cardiac hypertrophy, or abnormal growth of the heart. Finding ways to avert hypertrophy has emerged as a research priority. The endocannabinoid system is of interest as a therapeutic target for a variety of disorders. We will focus on the cannabinoid (CB) receptors, as we found that drugs which activate CB receptors block hypertrophy. Unfortunately, these drugs also act in the brain to cause side effects such as dysphoria, memory impairment, and possibly addiction. We will focus on CB receptor activators that are devoid of psychoactive side effects. We hypothesize that these drugs will protect against hypertrophy. We will study the mechanisms that mediate the ability of CB activators to inhibit hypertrophy using an established model of hypertrophy - heart muscle cells that are treated with a growth stimulus. We identified targets at which CB signaling might be interfering, and the effects of CB signaling on these targets will be pursued by genetic, biochemical, and imaging techniques. We will next verify that findings realized in cells are relevant to intact animals. We will generate hypertrophy in mice by placing a band on the aorta, and assess the effects of CB-activating drugs on hypertrophy and relevant signaling pathways. The incidence of heart failure is predicted to double by 2025, so we are striving to prevent the transition from hypertrophy to heart failure. By learning how CB receptors might control this transition while avoiding adverse side effects, we may discover molecular targets that can be manipulated for therapeutic gain to treat heart disease.