Thrombospondins in the transition from myocardial infarction to heart failure

Abstract

The heart's reaction to ischemic injury from a myocardial infarction involves complex cross-talk between the extra-cellular matrix (ECM) and different cell types within the myocardium. The ECM functions not only as a scaffold where myocytes beat synchronously, but an active signaling environment that regulates the important post-MI responses. The thrombospondins are matricellular proteins that modulate cell--ECM interactions, functioning as "sensors" that mediate outside-in and inside-out signaling. Thrombospondins are highly expressed during embryonic stages, and although their levels decrease during adult life, can be re-expressed in high quantities in response to cardiac stress including myocardial infarction and heart failure. Like a Swiss-army knife, the thrombospondins possess many tools: numerous binding domains that allow them to interact with other elements of the ECM, cell surface receptors, and signaling molecules. It is through these that the thrombospondins function. In the present review, we provide basic as well as clinical evidence linking the thrombospondin proteins with the post myocardial infarction response, including inflammation, fibrotic matrix remodeling, angiogenesis, as well as myocyte hypertrophy, apoptosis, and contractile dysfunction in heart failure. We will describe what is known regarding the intracellular signaling pathways that are involved with these responses, paving the road for future studies identifying these proteins as therapeutic targets for cardiac disease.

Keywords: Angiogenesis; Heart failure; Myocardial infarction; Remodeling; TGFβ; Thrombospondin.

Figure 1. Structure of the two thrombospondin (TSP) subgroups

Subgroup A form homotrimers and consist of TSP-1 and TSP-2, while Subgroup B form homopentamers and consist of TSP-3, TSP-4, and TSP-5 (COMP). Subgroup A has domains that bind to CD36 and inhibit MMPs. The N-terminal domains tend to be family member specific, while the CTD has high homology between the family members. NTD: N-terminal domain (specific to each family member), vWF-C: von Willebrand factor C-type domain, MMP: matrix metalloproteinase, EGF: epidermal growth factor, CTD: C-terminal domain.

Figure 2. The TSPs regulate inflammation and fibrotic matrix remodeling post MI

As matricellular proteins, the TSP family interacts with multiple different cells types in the myocardium to induce their effects. TSP-1 and TSP-2 affect remodeling through their interactions with transforming growth factor β (TGFβ) and it’s signaling in fibroblasts, matrix metalloproteinases (MMPs), and interactions with CD47 on T-cells. TSP-4 is suggested to be pro-inflammatory (opposite of TSP-1/2) through interactions with macrophages. Moreover, TSP-4 can inhibit collage production (possibly through direct binding and interaction), and this may involve krüppel-like factor 6 (KLF6) transcriptional regulation of TSP-4.

Figure 3. TSP1 and TSP2 are anti-angiogenic, while TSP-4 is pro-angiogenic

Both TSP-1 and TSP-2 provide their anti-angiogenic properties by binding to CD36 via their Type I repeats. Subsequent signaling through Src, Fyn, JNK, Fas, and others results in apoptotic/anti-angiogenic effects. While it is known that TSP-4 has pro-survival and pro-angiogenic capabilities, opposite those of TSP-1 and TSP-2, the mechanisms are less clear. Lacking the Type I repeats of the Subgroup A TSP trimers, TSP-4 doesn’t posses the CD36 binding domain. Recent evidence suggests the integrin α₂ and gabapentin receptor α₂δ-1, but beyond that the signaling is currently unknown.

Figure 4. Recent work has identified several roles for TSPs once the heart has transitioned to heart failure

The effects the TSPs have on matrix remodeling and inflammation are still important in heart failure. However, they also regulate a number of pathophysiologically important elements within the cardiac myocyte, which exhibits hypertrophy, apoptosis, and contractile dysfunction with HF. However, our knowledge of the mechanistic function of each of the TSPs in the HF myocyte is still incomplete.

Figure 5. Thrombospondin-4 is necessary for the heart’s response to acute changes in volume/length

The slow force response occurs when a myocyte experiences stretch, often on the order of 5–6%. The acute phase of the pressure overload also stretches the myocytes. In normal mice, stretch causes a nearly instantaneous increase in force via the Frank-Starling (FS) mechanism, and then a steady increase in force over the following 15 minutes known as the slow-force response, or Anrep Effect. In the thrombospondin-4 knockout (TSP-4 KO) mice, the FS mechanism is intact, but the slow-force response is absent. In fact, force decreases slightly in response to stretch (red line). Figure adapted from [97].