Intermedin Suppresses Pressure Overload Cardiac Hypertrophy through Activation of Autophagy

Abstract

Left ventricular hypertrophy is a maladaptive response to pressure overload and an important risk factor for heart failure. Intermedin (IMD), a multi-functional peptide, plays important roles in cardiovascular protection. In this study, we revealed an autophagy-dependent mechanism involved in IMD’s protection against cardiac remodeling and cardiomyocyte death in heart hypertrophy. We observed that transverse aortic contraction (TAC) induction, Ang II or ISO exposure induced remarkable increase in the expression of endogenous IMD and its receptor components, CRLR, RAMP1 and RAMP3, in mouse hearts and H9c2 cell cultures, respectively. Furthermore, the heart size, heart weight/body weight ratios, cardiomyocyte size and apoptosis, interstitial collagen, hypertrophic markers including ANP and BNP expression were also significantly increased, which were effectively suppressed by IMD supplementation. In addition, IMD induced capillary angiogenesis and improved functions in hypertrophic hearts. We further observed that IMD induced strong autophagy in hypertrophic hearts and cultured cells, which was paralleling with the decrease in cardiomyocyte size and apoptosis. Furthermore, an autophagy inhibitor, 3-MA, was used to block the IMD-augmented autophagy level, and then the protection of IMD on cardiomyocyte hypertrophy and apoptosis was almost abrogated. We also observed that IMD supplementation stirred intracellular cAMP production, and augmented the ERK1/2 phosphorylation induced by Ang II/ISO exposure in H9c2 cells. In addition, we inhibited PI3K, PKA and MAPK/ERK1/2 signaling pathways by using wortamannin, H89 and PD98059, respectively, in H9c2 cells co-incubating with both IMD and Ang II or ISO, and observed that these inhibitors effectively reduced IMD-augmented autophagy level, but only H89 and PD98059 pre-incubation abrogated the anti-apoptotic action of IMD. These results indicate that the endogenous IMD and its receptor complexes are induced in hypertrophic cardiomyocytes and proposed to play an important role in the pathogenesis of cardiac hypertrophy, and the autophagy stirred by IMD supplementation is involved in its protection against cardiomyocyte hypertrophy and apoptosis through the activation of both cAMP/PKA and MAPK/ERK1/2 pathways.

Intermedin 1− 53 Attenuates Abdominal Aortic Aneurysm by Inhibiting Oxidative Stress

“…29 We first examined changes in IMD and its receptor in the Ang II-or CaCl 2 -induced AAA mice model. Consistent with the results of IMD in cardiac hypertrophy 30 or ADM in patients with arteriosclerosis, 13 we found a marked increase in IMD protein level in Ang II-induced AAA mouse aortas and plasma.…”

“…The actions of IMD are associated with the activation of cAMP, and cAMP/PKA is the main pathway of IMD exerting its effect. The potective effects of IMD in cardiac hypertrophy 30 and vascular calcification 46 were attributed to the activation of cAMP/PKA signaling, which support our finding that the activation of cAMP/PKA may play a part in IMD downregulated Nox4 expression. The underlying molecular basis of IMD downregulated Nox4 expression should be further explored.…”

“…Compensatory upregulation of endogenous IMD in vessels may play a protective role in AAA. 30 Furthermore, the upregulated mRNA and protein levels of CRLR/RAMP3 in AAA mouse aortas indicated that the special receptor complexes of IMD/CRLR/RAMP3 were enhanced in the presence of Ang II-induced AAA. In CaCl 2 -induced AAA, the protein level of IMD was upregulated in aortas but was reduced in plasma in the early stage of AAA.…”

“…The mRNA levels of its receptors CRLR and RAMPs were all increased at 7 days after the periaortic incubation of CaCl 2 , then recovered to a normal level at later times. The expression profile of IMD and its receptors varies by disease state, and stage of disease, 17,30 which may explain the different changes in expression of IMD and its receptors in the 2 AAA models or at different stages of CaCl 2 -induced AAA. In all, the changes of IMD level and its receptor in the systemic imbalance and local damage-induced AAA suggest that this peptide acts as a regulatory autocrine or paracrine modulator of AAA and may have a protective role in AAA.…”

The role of autophagy in angiotensin II-induced pathological cardiac hypertrophy

“…PI3K inhibition by wortmannin, PKA inhibition by H89 or MAPK/ ERK1/2 inhibition by PD98059 effectively reduced the intermedin-augmented autophagy level in Ang II-exposed H9c2 cells, but only H89 and PD98059 pre-incubation abolished the antiapoptotic action of intermedin. All these results indicate that the endogenous intermedin induced by Ang II may play an important role in cardiac hypertrophy, and the augmented autophagy level induced by intermedin supplementation is involved in its protection against cardiomyocyte hypertrophy through the activation of both MAPK/ERK1/2 and cAMP/PKA signaling pathways (Chen et al 2013). Other signaling pathways are also found in the regulation of autophagy in the Ang II-induced cardiac hypertrophy; for example, class I PI3K, via the activation of the Akt/mTOR pathway, is involved in Ang II-induced impairment of autophagy, elevation of ROS, cardiac hypertrophy and fibrosis (Yan et al 2015b).…”