The α 1A‐adrenergic receptor mediates cardiac hypertrophy through the G α q‐PI3K‐Rac1 signaling pathway

Using a mouse model of cardiac‐specific over‐expression of the α 1A ‐adrenergic receptor (α 1A ‐AR; α 1A ‐M 66‐fold; α 1A ‐H 166‐fold) we have recently shown that acute activation of the α 1A ‐AR results in enhanced contraction through activation of α 1A ‐AR‐operated Ca 2+ entry via Snapin and TRPC6. We have now defined a hypertrophic signalling pathway involving α 1A ‐AR‐mediated recruitment of Gα q ‐PI3K‐Rac1 that is distinct from the contractile pathway. Cardiomyocytes from adult α 1A ‐M, α 1A ‐H and WT mice stimulated with the α 1A ‐AR‐specific agonist A61603 exhibited dose‐dependent increases in hypertrophic gene expression, protein synthesis, and cell surface area that were proportional to the level of receptor expression and were Gα q ‐PI3K‐Rac1‐dependent. Inhibition of the α 1A ‐AR contractile pathway by blockade of TRPC6 did not inhibit α 1A ‐AR‐mediated induction of cardiac hypertrophy. The elucidation of two distinct α 1A ‐AR‐mediated signalling pathways, one increasing cardiac contraction upon acute activation and the other inducing cardiac hypertrophy upon chronic activation, identifies the α 1A ‐AR as a potential target for the development of pathway‐specific α 1A ‐AR‐agonist drugs to treat heart failure. Sponsor: NHMRC, NHF